Clinical trial NCT01134601
Conditions: Non-Metastatic Adenocarcinoma of the Rectum
Keywords: Rectal Cancer Radiation Therapy Capecitabine AZD6244
Sponsor: National Cancer Institute (NCI)
Start date: 2010-05-24; Completion date: 2012-10-22
Enrollment: 1 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Background:

\- The investigational anti-cancer drug Selumetinib (AZD6244) prevents a protein found in rectal cancer from working properly, which may slow tumor growth and allow radiation and chemotherapy treatments to destroy more cancer cells. Researchers are interested in determining whether AZD6244 can be used to improve treatment outcomes in individuals who have rectal cancer that has spread outside the rectum into the surrounding pelvis.

Objectives:

\- To determine safe and effective doses of AZD6244, along with radiation and chemotherapy, to treat rectal cancer.

Eligibility:

\- Individuals at least 18 years of age who have been diagnosed with rectal cancer that has spread outside the inner wall of the rectum or into lymph nodes in the pelvis.

Design:

* Eligible participants will be screened with a physical examination, blood and tumor samples, and imaging studies.
* Participants will receive AZD6244 twice a day by mouth for 1 full week (7 days) before starting radiation and chemotherapy and every week thereafter until the end of the radiation and chemotherapy treatment.
* Participants will have radiation therapy daily, 5 days per week, for approximately 6 weeks.
* Participants will receive chemotherapy (capecitabine) twice daily, 5 days per week, for approximately 6 weeks.
* Approximately 4 to 8 weeks after completing the AZD6244, radiation, and chemotherapy treatment, participants may have surgery to remove any tumors and affected lymph nodes. This surgery is not part of the treatment delivered on this protocol.
* Participants will have a follow-up exam 3 weeks after the end of treatment, every 3 months for the first year, and then in the second and third year after the end of treatment. These visits will involve a full medical examination and imaging studies.

Detailed description:
Background:

* Local recurrences of rectal cancer are morbid and difficult to manage effectively.
* Colorectal cancers frequently harbor rat sarcoma (RAS) mutations and Epidermal growth factor (EGF)/epidermal growth factor receptor (EGFR) over-expression.
* AZD6244 is an orally available selective, adenosine triphosphate uncompetitive inhibitor of methyl ethyl ketone (MEK)1/2 that sensitizes tumor cells to radiation in vitro and in vivo.

Objectives:

Primary

* To define the maximum tolerable dose of AZD6244 Hyd-Sulfate delivered twice a day (BID), 7 days per week, in combination with radiation therapy (RT) and Capecitabine in patients with locally advanced adenocarcinoma of the rectum without distant metastases.
* To define the dose-limiting toxicities and toxicity profile associated with administration of AZD6244 Hyd-Sulfate delivered BID, 7 days per week in combination with RT and Capecitabine

Secondary

* To evaluate the pharmacokinetics of AZD6244 delivered alone and in combination with Capecitabine 825 mg/m(2) by mouth (PO) BID.
* To obtain exploratory information regarding the pathologic response rate obtained after treatment with the maximum tolerated dose (MTD) of AZD6244 Hyd-Sulfate in combination with Capecitabine and 50.4 Gray (Gy) of RT.
* To determine if changes in phosphorylated extracellular-signal regulated kinase (ERK) (pERK) in peripheral blood mononuclear cells correlates to changes in phosphorylated extracellular-signal regulated kinase (pERK) in rectal tumors in the setting of treatment with AZD6244.
* To perform an exploratory analysis to determine if the presence of activating mutations in RAS or BRAF in tumor or changes in plasma transforming growth factor-alpha (TGFalpha) levels and tumor pERK/total ERK with AZD6244 treatment alone and after AZD6244 in combination with Capecitabine and RT predicts for down staging or pathologic response.

Eligibility:

* Histologically or cytologically confirmed locally advanced, non-metastatic adenocarcinoma of the rectum (clinical stage T3AnyN, T4AnyN, or AnyTN+).
* Age greater than or equal to 18 years.
* Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2.
* Normal organ and marrow function.

Design:

* All patients will receive 50.4 Gy of RT to the pelvis and rectal tumor delivered concurrently with Capecitabine and AZD6244. AZD6244 will be delivered BID daily, 7 days per week, in a dose escalated fashion. AZD6244 will begin one week prior to Capecitabine and RT and will conclude on the last day of Capecitabine and RT.
* Capecitabine will be delivered at 825 mg/m(2) PO every 12 hours, 5 days per week, starting on the first day of RT and continuing until the last day of RT.
* Biopsies of tumor tissue will be obtained prior to treatment, after one week of AZD6244, and after one week of AZD6244, RT, and Capecitabine for correlative assays.

Arms: arm 1: LEVEL 1 - Cycle = 49 days: AZD6244: 50 mg by mouth (PO) everyday (QD) Capecitabine: 825 mg/m\^2 by mouth (PO)
Interventions: intervention 1: Radiation Therapy intervention 2: Capecitabine intervention 3: AZD6244
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None

Protocol documents:
Prot_SAP_000.pdf: 
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TITLE:  A Phase I Study of AZD6244 in Combination with 
Capecitabine and Radiotherapy in Locally Advanced Adenocarcinoma of the Rectum 
 
*Principal Investigator: 
Deborah Citrin, M.D. 
 
Radiation Oncology Branch, NCI 
 
10 CRC, B2-3500 
 
10 Center Drive 
 
Bethesda, MD 20892 
 
(301) 496-5457 
 
(301) 480-5439 
 
citrind@mail.nih.gov 
 
Co-Investigators: 
Kevin Camphausen, M.D. 
 
Radiation Oncology Branch, NCI 
 
10 CRC, B2-3500 
 
10 Center Drive 
 
Bethesda, MD 20892 
 
(301) 496-5457 
 
(301) 480-5439 
 
camphauk@mail.nih.gov 
 
 
Aradhana Kaushal, M.D. 
 
Radiation Oncology Branch, NCI 
 
10 CRC, B2-3500 
 
10 Center Drive 
 
Bethesda, MD 20892 
 
(301) 496-5457 
 
(301) 480-5439 
 
kaushala@mail.nih.gov 
 
 
 
Shivaani Kummar, MD 
 
Medical Oncology Branch, NCI 
 
Bulding10, 13N240G 
 
10 Center Drive 
 
Bethesda, MD 20892 
 
(301) 435-5402 
 
Fax (301)402-0172 
 
kummars@exchange.nih.gov 
 
 
Austin Duffy, MD 
 
Medical Oncology Branch, NCI 
 
10 CRC, 5-5561 
 
10 Center Drive 
 
Bethesda, MD 20892 
 
(301) 451-8340 
 
Fax (301)402-0172 
 
duffya@mail.nih.gov 
 
 
 
 


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Martha Quezado, MD 
Laboratory of Pathology, NCI 
Bldg 10 Rm 2B50D 
10 Center Drive 
Bethesda, MD 20892 
 
(301) 496- 4724 
 
Fax (301) 480- 9488 
 
zquezado@mail.nih.gov 
 
 
Itzhak Avital, MD 
Surgery Branch, NCI 
10 CRC, 3-3940 
10 Center Drive 
Bethesda, MD 20892 
 
(301) 496-4164 
 
Fax (301) 402-1788 
avitali@mail.nih.gov 
 
Sharon Smith, RN, MS  
10 CRC, B2-3500  
10 Center Drive 
Bethesda, MD 20892 
 
(301) 496-5457 
 
Fax (301) 480-2347  
 
smiths@mail.nih.gov 
 
 
Statistician: 
 
Joanna Shih, PhD 
Biostatistics and Data Management Section 
Office of the Clinical Director, CCR, NCI 
6130 Executive Blvd, EPN8132, MSC 8325 
Bethesda MD 20892-8325 
301-443-1607 
Fax: 301-402-0560 
jshih@mail.nih.gov  
 
Responsible Research Nurse:  
Debbie McNally, RN 
 
10 CRC, B2-3500  
10 Center Drive 
Bethesda, MD 20892 
 
(301) 496-5457 
 
Fax (301) 480-2347  
 
cooleyd@mail.nih.gov  
 
NCI Supplied Agent(s):                  AZD6244 (NSC 748727; IND # 77, 782) 
 
 
Capecitabine, Clinical Center Pharmacy, NIH 
 
Protocol Type / Version # / Version Date: Phase I / Version 7 / 10/24/2011


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Précis 
Background: 
• Local recurrences of rectal cancer are morbid and difficult to manage effectively. 
• Colorectal cancers frequently harbor RAS mutations and EGF/EGFR over-expression.  
• AZD6244 is an orally available selective, adenosine triphosphate–uncompetitive inhibitor of 
MEK1/2 that sensitizes tumor cells to radiation in vitro and in vivo. 
 
Objectives: 
Primary 
• To define the maximum tolerable dose of AZD6244 Hyd-Sulfate delivered BID, 7 days per 
week, in combination with radiation therapy (RT) and Capecitabine in patients with locally 
advanced adenocarcinoma of the rectum without distant metastases. 
• To define the dose-limiting toxicities and toxicity profile associated with administration of 
AZD6244 Hyd-Sulfate delivered BID, 7 days per week in combination with RT and 
Capecitabine 
 
Secondary 
• To evaluate the pharmacokinetics of AZD6244 delivered alone and in combination with 
Capecitabine 825 mg/m2 PO BID. 
• To obtain exploratory information regarding the pathologic response rate obtained after 
treatment with the MTD of AZD6244 Hyd-Sulfate in combination with Capecitabine and 
50.4 Gy of RT. 
• To determine if changes in phosphorylated ERK (pERK) in peripheral blood mononuclear 
cells correlates to changes in pERK in rectal tumors in the setting of treatment with 
AZD6244. 
• To perform an exploratory analysis to determine if the presence of activating mutations in 
RAS or BRAF in tumor or changes in plasma transforming growth factor-α (TGFα) levels and 
tumor pERK/total ERK with AZD6244 treatment alone and after AZD6244 in combination 
with Capecitabine and RT predicts for down staging or pathologic response. 
 
Eligibility: 
• Histologically or cytologically confirmed locally advanced, non-metastatic adenocarcinoma of 
the rectum (clinical stage T3AnyN, T4AnyN, or AnyTN+). 
• Age >18 years.   
• ECOG performance status <2. 
• Normal organ and marrow function. 
 
Design: 
• All patients will receive 50.4 Gy of RT to the pelvis and rectal tumor delivered concurrently 
with Capecitabine and AZD6244.  AZD6244 will be delivered BID daily, 7 days per week, in a 
dose escalated fashion. AZD6244 will begin one week prior to Capecitabine and RT and will 
conclude on the last day of Capecitabine and RT. 
• Capecitabine will be delivered at 825 mg/m2 PO every 12 hours, 5 days per week, starting on 
the first day of RT and continuing until the last day of RT. 
• Biopsies of tumor tissue will be obtained prior to treatment, after one week of AZD6244, and 


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after one week of AZD6244, RT, and Capecitabine for correlative assays.


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SCHEMA 
 
 


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TABLE OF CONTENTS 
 
 
Page 
PRECIS…………………………………………………………………………………………… 
3 
SCHEMA ......................................................................................................................................................................................... 5 
 
1. 
OBJECTIVES ......................................................................................................................................................................... 8 
 
1.1  
Primary Objectives .................................................................................................................................................... 8 
 
1.2  
Secondary Objectives ................................................................................................................................................ 8 
 
2. 
BACKGROUND ..................................................................................................................................................................... 8 
 
2.1  
AZD6244 .................................................................................................................................................................. 8 
 
2.2  
Other Agent(s) ........................................................................................................................................................ 18 
 
2.3  
Locally Advanced Adenocarcinoma of the Rectum ................................................................................................ 18 
 
2.4  
Rationale ................................................................................................................................................................. 19 
 
2.5 
Correlative Studies Background ............................................................................................................................. 23 
 
3. 
PATIENT SELECTION ....................................................................................................................................................... 27 
 
3.1  
Eligibility Criteria  .................................................................................................................................................. 27 
 
3.2  
Exclusion Criteria ................................................................................................................................................... 28 
 
3.3  
Research Eligibility Evaluation ............................................................................................................................... 29 
 
3.4  
Registration Procedures .......................................................................................................................................... 30 
 
4. 
TREATMENT PLAN ........................................................................................................................................................... 30 
 
4.1  
Agent Administration .............................................................................................................................................. 30 
 
 
4.1.1  AZD6244 .............................................................................................................................................................. 30 
 
 
4.1.2  Capecitabine ......................................................................................................................................................... 32 
 
 
4.1.3  Radiation Therapy ................................................................................................................................................. 32 
 
 
4.1.4  Surgery .................................................................................................................................................................. 33 
 
4.2  
Definition of Dose-Limiting Toxicity ..................................................................................................................... 33 
 
4.3 
General Concomitant Medication and Supportive Care Guidelines ........................................................................ 34 
 
4.4  
Duration of Therapy ................................................................................................................................................ 35 
 
4.5  
Duration of Follow Up ............................................................................................................................................ 35 
4.6 
Criteria for Removal from Study............................................................................................................................. 35 
 
5. 
DOSING DELAYS/DOSE MODIFICATIONS .................................................................................................................. 36 
 
6. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................................................................ 38 
 
6.1 
Definitions............................................................................................................................................................... 38 
 
6.2 
Comprehensive Adverse Events and Potential Risks Lists (CAEPRs) .................................................................... 40 
 
6.3 
Adverse Event Characteristics ................................................................................................................................ 43 
 
6.4 
Expedited Adverse Event Reporting ....................................................................................................................... 43 
 
6.5 
IND Sponsor Reporting........................................................................................................................................... 47 
 
6.6 
FDA Reporting Criteria........................................................................................................................................... 47 
 
6.7 
Secondary AML/MDS ............................................................................................................................................ 48 
 
6.8  
Data and Safety Monitoring Plan ............................................................................................................................ 48 
7. 
HUMAN SUBJECTS PROTECTION ................................................................................................................................ 48 
 
7.1 
Rationale for Subject Selection ............................................................................................................................... 49 
 
7.2 
Justification for Exclusion ....................................................................................................................................... 49 
 
7.3 
Participation of Children ......................................................................................................................................... 49 
 
7.4 
Evaluation of Benefits and Risks/Discomforts………………………………………………………………........  49 
 
7.5 
Consent and Assent Process and Documentation………………………………………………………………. …50 
 
7.6 
Procedures for Protecting Against or Minimizing Any Potential Risks .................................................................. 50 
 
8. 
PHARMACEUTICAL INFORMATION ........................................................................................................................... 50 
 
8.1  
AZD6244 ................................................................................................................................................................ 51 
 
8.2  
Capecitabine ........................................................................................................................................................... 52 
 
9. 
CORRELATIVE/SPECIAL STUDIES ............................................................................................................................... 53 
9.1 
Laboratory Correlative Studies ............................................................................................................................... 53 
9.2 
Sample Processing .................................................................................................................................................. 53 


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10. STUDY CALENDAR ........................................................................................................................................................... 55 
 
11. MEASUREMENT OF EFFECT .......................................................................................................................................... 56 
11.1 
Disease progression ................................................................................................................................................ 56 
11.2 
Other Response Parameters .................................................................................................................................... 60 
 
12.  DATA REPORTING / REGULATORY REQUIREMENTS ............................................................................................ 60 
 
12.1 Data Reporting ................................................................................................................................................................ 60 
 
12.2 Cooperative Research and Development Agreement (CRADA)/ 
 
 
 
Clinical Trials Agreement (CTA) ............................................................................................................................ 61 
 
13. STATISTICAL CONSIDERATIONS ................................................................................................................................. 62 
 
REFERENCES ............................................................................................................................................................................. 66 
 
INFORMED CONSENT ..................................................................................................................................................................  
 
APPENDICES 
 
APPENDIX A 
Performance Status Criteria ............................................................................................................................................ 69 
 
APPENDIX B 
New York Heart Association Classifications .................................................................................................................. 70 
 
APPENDIX C 
Medications That May Cause QTc Prolongation ............................................................................................................ 71 
 
APPENDIX D 
Patient’s Medication Diary ............................................................................................................................................. 73 
 
APPENDIX E 
Laboratory Studies Correlative Background ................................................................................................................... 75 
 
APPENDIX F 
        RTOG Acute Toxicity Scoring Schema  ......................................................................................................................... 76 
 
APPENDIX G 
        RTOG Late Toxicity Scoring Schema  ........................................................................................................................... 77


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1. OBJECTIVES 
 
1.1. 
Primary Objectives 
 
• To define the maximum tolerable dose of AZD6244 Hyd-Sulfate delivered BID, 7 days 
per week, in combination with radiation therapy and Capecitabine in patients with 
locally advanced adenocarcinoma of the rectum without distant metastases. 
 
• To define the dose-limiting toxicities and toxicity profile associated with administration 
of AZD6244 Hyd-Sulfate delivered BID, 7 days per week in combination with radiation 
therapy and Capecitabine 
 
1.2. 
Secondary Objectives 
 
• To determine if changes in phosphorylated ERK (pERK) in peripheral blood 
mononuclear cells correlates to changes in pERK in rectal tumors in the setting of 
treatment with AZD6244. 
 
• To obtain exploratory information regarding the pathologic complete response rate 
(pCR) obtained after treatment with the MTD of AZD6244 Hyd-Sulfate in combination 
with Capecitabine and 50.4 Gy of radiation. 
 
• To determine if a reduction in phosphorylated ERK (pERK) in peripheral blood 
mononuclear cells correlates to similar changes in ERK phosphorylation in rectal 
tumors in the setting of treatment with AZD6244. 
 
• To perform an exploratory analysis to determine if the presence of activating mutations 
in RAS or BRAF in tumor or changes in plasma transforming growth factor-α (TGFα) 
levels and tumor pERK/total ERK with AZD6244 treatment alone and after AZD6244 
in combination with Capecitabine and radiation predicts for tumor/nodal down staging 
or pCR 
 
2. BACKGROUND 
 
2.1  
AZD6244 
AZD6244 (ARRY-142886) is a potent, selective, orally-available, and non-ATP competitive 
small molecule inhibitor of the mitogen-activated protein (MAP) kinase kinase, MEK-1/2.(1)  
AZD6244 inhibited the activity of purified MEK enzyme with an IC50 of 10-14 nM, and was 
found to be inactive or minimally active at 10 μM against a panel of other kinases, including 
epidermal growth factor receptor (EGFR), erbB2, p38α, ERK2, and MKK 6 kinases.  
Because ERK is the only known substrate of MEK, the inhibition of MEK will target only 
the ERK signal transduction pathway and other signal transduction pathways will not be 
blocked.  AZD6244 is metabolized to biologically active N-desmethyl AZD6244 which is 
more potent than the parent compound.  In vitro, in vivo and preliminary results from clinical 
studies suggest that AZD6244 exhibits a favorable pharmacologic and toxicologic profile. 
 


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The RAS/RAF/MEK/ERK signaling pathway plays a central role in the regulation of many 
cellular processes including proliferation, survival, differentiation, apoptosis, motility, and 
metabolism.(2, 3)  This pathway is one of the most important and best understood MAP 
kinase signal transduction pathways, activated by a diverse group of extracellular signals 
including integrins, growth factor receptors (i.e., EGFR, platelet-derived growth factor 
receptor [PDGFR], and insulin-like growth factor-1 receptor), and cytokines.(4)  Activated 
RAS triggers the phosphorylation and activation of RAF kinase which then phosphorylates 
MEK1 and MEK2 on 2 serine residues.(5) Activated MEK phosphorylates its only known 
substrates, ERK1 and ERK2.  Phosphorylated ERK dimerizes and translocates to the 
nucleus(6) where it is involved in several important cellular functions, including cell 
proliferation.  
 
Overexpression of growth factors or growth factor receptors involved in the 
RAS/RAF/MEK/ERK pathway and activating genetic mutations of the signaling proteins 
may lead to uncontrolled proliferation and tumor formation.  For example, RAS genes are the 
most frequently mutated oncogenes detected in human tumors.(4)  RAS proteins are guanine 
nucleotide binding proteins that activate RAF proteins when bound to GTP.  Cancer-
associated mutations in RAS proteins stabilize the GTP-bound form of RAS, thereby 
providing a constitutive signal downstream in the cascade.  In addition to being found in 
almost all pancreatic adenocarcinomas, RAS mutations are found in ~50% of colorectal 
carcinomas, 25-50% of lung adenocarcinomas, and also in some breast or ovarian cancers.  
BRAF mutations have also been observed in many human cancers, particularly melanoma 
(30-60%), thyroid (30-50%), colorectal (5-20%), and ovarian (~30%) cancers.(7)  These 
mutations in BRAF usually involve gain-of-function substitutions that render the kinases 
constitutively active.  Also, studies of primary tumor samples and cell lines have shown 
constitutive activation or over-activation of the MAP kinase pathways in cancers of the 
pancreas, colon, lung, ovary, and kidney.(8)  Therefore, agents targeting the 
RAS/RAF/MEK/ERK pathway may inhibit oncogenic signaling in tumor cells.  
 
2.1.1 Nonclinical Studies 
2.1.1.1 Efficacy 
In vitro studies have shown that AZD6244 and its N-desmethyl metabolite are potent 
and selective inhibitors of MEK.(9)  However, significant biochemical activity was 
not detected when the two compounds were tested against a diverse panel of 305 
other molecules, including enzymes, receptors, kinases, transporters, and ion 
channels.  The effects of AZD6244 on ERK phosphorylation and cell viability were 
determined in a panel of cell lines in which the mutational status of RAF and RAS are 
known.  AZD6244 inhibited ERK1 and ERK2 phosphorylation with IC50s ranging 
from 0.0018 to 0.041 μM.  AZD6244 was particularly potent in inhibiting the cell 
viability of cell lines with V600E BRAF gene mutation and some cell lines with 
KRAS mutations.  The N-desmethyl metabolite was found to be 3-fold more active 
than the parent compound in inhibiting ERK phosphorylation, and 5-fold more potent 
in inhibiting cell viability.  
 
Significant suppression of tumor growth in response to AZD6244 treatment was 


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observed in several xenograft mouse models derived from a range of tumor types 
including melanoma, breast, pancreatic, lung, colon, and hepatocellular 
carcinomas.(1, 9)  In the Calu-6 lung cancer xenograft model, AZD6244 suppressed 
tumor growth at doses of 10, 25, or 100 mg/kg given twice daily, and the minimal 
effective dose was identified as 0.75 mg/kg administered twice daily.  In this model, 
MEK activity was inhibited as assessed by determination of phosphorylated ERK 
(pERK) levels in tumor.  Studies using human colorectal xenograft models (SW620, 
Colo205) demonstrate that AZD6244 inhibits tumor growth by inhibition of cell 
proliferation and by induction of apoptosis.  
2.1.1.2  Pharmacokinetic/Pharmacodynamic Studies 
Oral bioavailability of AZD6244 was favorable in rats (37% at 10 mg/kg) and 
monkeys (86% at 1 mg/kg), but bioavailability decreased with increasing dose.(9)  
The declining bioavailability at higher doses may be due to the low aqueous solubility 
of AZD6244.  No accumulation of AZD6244 was observed following multiple dosing 
in rats or monkeys.  Studies in rats indicate that AZD6244 is widely distributed, 
although tissue concentrations were lower than blood concentrations.  High levels of 
protein binding (93.7-99.7%) were observed in all preclinical species tested and in 
humans (98.4%).  AZD6244 was excreted rapidly within 48 hours via the feces. 
 
The value of pERK as a biomarker of AZD6244 efficacy has been explored in 
nonclinical studies.  In the Calu-6 human lung cancer xenograft model, levels of 
pERK in the tumors were determined by both immunohistochemical (IHC) staining 
of formalin-fixed tissue sections and by western blot analysis of tumor protein 
lysates.(9)  Following an acute tumor-suppressive dose of 25 mg/kg of AZD6244, 
immunostaining for pERK in the cytoplasm was reduced by approximately 90% at 1, 
2 and 4 hours post-dose, and recovered to >50% of the level of the control by 24 
hours.  The increase in tumor pERK content by 24 hours correlated with the decrease 
in plasma concentration of AZD6244.  The same trend was observed by western blot 
analysis.  These data showed that tumor pERK levels are a potential biomarker for 
AZD6244 activity in vivo.   
 
A whole blood fluorescence-activated cell sorting (FACS) assay was developed to 
monitor pERK levels in peripheral blood mononuclear cells (PBMCs) to allow 
assessment of AZD6244 activity without tissue biopsy.(9)  Whole blood samples 
from cynomolgus monkeys at pre-dose and 1, 2, 4, 8, 12 hours post-dose were 
analyzed for pERK levels.  Plasma concentrations of AZD6244 correlated with 
inhibition of TPA-induced ERK phosphorylation.  Similarly, the ex vivo addition of 
AZD6244 to human whole blood from volunteers resulted in the inhibition of ERK 
phosphorylation in isolated PBMCs.  Data from an ongoing phase 1 study in cancer 
patients also indicate that there is a strong correlation between plasma drug 
concentration and inhibition of ERK phosphorylation in blood from these patients, 
demonstrating the effectiveness of pERK as a mechanistic biomarker for MEK 
inhibition in the clinical setting.(10) 
 
2.1.1.3  Toxicologic Studies 


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The toxicologic effects of AZD6244 were evaluated in acute dose (single or two 
doses on a single day) and 1-month, repeat-dose studies in Sprague-Dawley rats and 
cynomolgus monkeys.(9)  The repeat-dose study in rats indicated that the agent was 
well tolerated but produced soft stools and gastrointestinal mucosal mineralization 
associated with increased serum phosphorus and decreased albumin.  Diarrhea, 
dehydration, electrolyte imbalance, and secondary renal changes were observed in 
monkeys.  The vehicle, Captisol® (SBE-CD), used in the formulation is known to 
cause gastrointestinal disturbances in preclinical studies.  A reduction in the volume 
of Captisol® administration to monkeys was associated with a reduced incidence of 
diarrhea; however, it is likely that AZD6244 exacerbated the vehicle effects.  The no 
observable adverse effect levels (NOAEL) in rats and monkeys in the 1-month studies 
were identified as 10 mg/kg/day and 20 mg/kg/day (administered twice daily), 
respectively.  AZD6244 and its active metabolite showed no evidence of mutagenic 
potential, but AZD6244 produced an increase in micronucleated immature 
erythrocytes in mice, predominantly via an aneugenic mode of action.  
Safety pharmacology studies were performed to assess the effects of AZD6244 and 
its active metabolite on key organ systems.(9)  The agents did not produce any 
toxicologically significant effect.  Evidence of gastric mucosal lesions and minor 
increases in airway resistance were observed in some rats following a 100 mg/kg 
dose; however, these effects were not apparent in the 1-month study. 
 
 
 
2.1.2  Clinical Experience 
The clinical experience is summarized from the AZD6244 Investigator Brochure Version 
8.(11)  A number of clinical studies with AZD6244 have been completed or are ongoing.  
As of November 26, 2008 studies ARRY-0401, D1532C00003, D1532C00005, 
D1532C00008, D1532C00011, and D1532C00012 have been completed and 
D1532C00004 and D1532C00020 are ongoing.  In addition, six monotherapy trials of 
AZD6244 free-base are sponsored by the NCI for which no efficacy data is yet available.   
 
AZD6244 was initially dosed as a free-base suspension which was first evaluated in a 
single two-part, open-label, multicenter phase 1 company-sponsored study (ARRY-
0401).(9)  An MTD of 100 mg BID was achieved and subsequent Phase II trials with this 
preparation utilized this dosing regimen.  In the Phase II study D1532C00003 samples for 
plasma concentration analysis were collected.  In the Phase II study D1532C00005 the 
pharmacokinetics and relative bioavailability of the Hyd-Sulfate preparation compared to 
the free base suspension were evaluated.  The MTD for the Hyd-Sulfate preparation was 
determined to be 75 mg BID.  Further development of AZD6244 is intended to continue 
with the Hyd-Sulfate preparation.  
 
2.1.2.1  Pharmacokinetics 
N-desmethyl is the active metabolite of AZD6244, which is 3 to 5 times more potent 
to the parent compound.  An amide metabolite can also be detected in human plasma 
but is 40 to 50 fold less active than AZD6244.  Single dose pharmacokinetics of 
AZD6244 and N-desmethyl have been characterized following dosing of both the free 
base suspension (study ARRY-0401) for dose levels between 50 to 300 mg and the 


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Hyd-Sulfate preparation (D1532C00005) for dose levels between 25 to 100 mg. The 
parameters described below are those obtained with the Hyd-Sulfate preparation.  
AZD6244 was absorbed relatively quickly across dose levels, with a median tmax of 
1.5 hours. Plasma N-desmethyl AZD6244 concentrations/exposure followed a similar 
pattern to AZD6244 over time, although Cmax and AUC values were <15% of the 
parent within each patient. Following the peak, AZD6244 concentrations decreased 
multi-exponentially with a mean half-life (t½) of 5 to 7 hours.  The t½ of the N-
desmethyl metabolite was 9 to 13 hours.  Limited data is available for AZD6244 
amide.  Concentrations of this metabolite were variable within subjects and between 
subjects.  The time to maximum concentration was highly variable among patients. 
 
Study D1532C00020 evaluated the pharmacokinetics of AZD6244 in patients under 
fasting conditions and after a high fat meal.  Glsmean Cmax and AUC were reduced 
by approximately 60% and 20% under fed conditions compared to exposure 
following AZD6244 taken fasted.  There was a trend toward a later tmax in the fed 
condition.  Based on these findings it is recommended that AZD6244 should be taken 
on an empty stomach. 
 
Plasma pharmacokinetic parameters were similar for single and a multiple dosing 
(day 8, 15, and 22), suggesting minimal accumulation over time with twice daily 
dosing, consistent with the terminal half-life observed.  A similar pharmacokinetic 
profile was observed on day 8 compared to day 1 supporting that the steady state was 
achieved in this time.  The exposure of AZD6244 N-desmethyl followed a similar 
pattern.  Exposure on multiple dosing was comparable within patients.  Comparison 
of data from 7 or 14 days BID dosing suggest steady state was achieved by day 7. 
 
2.1.2.2  Safety 
The safety data presented reflects monotherapy safety data from ongoing and 
completed trials with both formulations of AZD6244.  It should be noted that there 
may be a different safety and tolerability profile for AZD6244 co-administered with 
other anti-cancer agents. 
 
Dermatological adverse events are frequently reported in association with 
administration of AZD6244, with dermatitis acneiform being the most commonly 
reported event starting within the first month of treatment. Other types of 
dermatological events occur only after a more prolonged period of administration 
with AZD6244, including skin fissures and palmar-plantar eythrodysaethesia (hand-
foot syndrome). Where the dermatological AE is CTCAE Grade 3 or above, or is 
intolerable CTCAE Grade 2, a dose holiday (either with or without dose reduction) 
may be required to bring the CTCAE intensity to within tolerable limits, although this 
may not result in total resolution of the symptoms whilst the patient is continuing to 
receive AZD6244. An algorithm for additional interventions for the management of 
dermatological adverse events has been adapted from clinical experience of 
management of similar dermatological effects of the EGFR tyrosine kinase inhibitor 
agents.(12, 13) The co-administration of AZD6244 with other anti-cancer agents, 
some of which are associated with dermatological adverse events, may result in a 


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higher frequency or intensity of these adverse events. Dermatologic adverse events 
have led to withdrawal of one patient from each of four AZD6244 studies (4 patients 
total). 
 
Diarrhea, nausea, and vomiting are consistent adverse event in AZD6244 trials.  The 
majority of events were CTCAE grade 1 for diarrhea and nausea or CTCAE grade 1 
or 2 for vomiting.  Fewer than 2% of patients reported a SAE of diarrhea, nausea, or 
vomiting with the exception that in the D1532C00005 study with the Hyd-Sulfate 
preparation SAE vomiting was reported by 7% of patients.  Most diarrhea events 
started within 2 weeks of BID dosing.  Approximately one third of patients with 
diarrhea required concomitant loperamide to manage diarrhea.  Approximately half of 
patients with nausea adverse events required concomitant medication to control 
symptoms. The co-administration of AZD6244 with other anti-cancer agents, some of 
which are associated with gastrointestinal adverse events, may result in a higher 
frequency or intensity of these events. 
 
Adverse events of fatigue are reported across all studies with AZD6244.  In the 
majority of cases the causality was split approximately equally between study drug 
and the disease under study.  A higher frequency of fatigue AEs were reported with 
the Hyd-Sulfate preparation compared to the free-base suspension in Phase II 
monotherapy trials (67.9% vs 20.8%).  A minority of fatigue events were CTCAE 
grade 3 with the highest frequency of 14% of patients in study D1532C0005 
including 1 DLT. 
 
Edema (primarily peripheral and periorbital) and fluid accumulation has been 
reported consistently in studies of AZD6244 with peripheral edema being most 
common.  The underlying etiology of the edema and fluid accumulation adverse 
events is unclear at present. There is currently no evidence to suggest that the edema 
is due to congestive cardiac failure. Most peripheral edema AEs were CTCAE grade 
1.  The time of onset was commonly several weeks into treatment with AZD6244.  
Some patients required initiation of diuretic therapy to control the peripheral edema.   
 
Some patients receiving AZD6244 have been observed to develop asymptomatic 
decreases in LVEF in the absence of obvious confounding comorbidities. The co-
administration of AZD6244 with other anti-cancer agents, some of which are known 
to be associated with cardiotoxicity, may be associated with an increased risk of 
impairment of cardiac function. There have been four AE reports of left ventricular 
dysfunction, two reports of ejection fraction decreased, and one report each of 
ventricular dysfunction and ventricular hypokinesia in patients receiving AZD6244 
free-base.  Two events of left ventricular dysfunction were considered SAEs.  In 
study D153200005 with the Hyd-Sulfate preparation LVEF was monitored and data 
indicate a trend toward a drop in LVEF across all dose cohorts by week 8 
assessments.  No comparator data is available and the study population included 
patients who may have received prior cardiotoxic chemotherapy. 
 
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Seven SAEs of dyspnea have been reported from trials of AZD6244 and all subjects 
had thoracic disease and/or disease progression at the time of the report. In study 
D1532C00005 with the Hyd-Sulfate preparation dyspnea and exertional dyspnea 
were reported by 3.8% and 28.6% of patients which are higher frequencies than 
observed with the free-base formulation.  Treatment related dyspnea events were 
generally reported several weeks after the start of BID dosing and the majority were 
CTCAE grade 1 to 2.  Hypoxia AEs all originated from a single study site at altitude.  
Three events of hypoxia were reported as treatment-related SAEs.  There has been 
one treatment-related SAE of pneumonitis but no other AEs of pneumonitis have 
been reported in any other completed study.  Preliminary unvalidated data indicates 
that one patient from study D1532C0020 has reported SAEs of lung infiltration and 
interstitial lung disease. 
 
Increases in SBP and DBP have been observed in clinical studies with AZD6244.  
AEs of hypertension have been reported by some patients treated with AZD6244.  In 
study D1532C00003 increases in blood pressure were observed after one week of 
treatment, with mean increases at 8 weeks of treatment of 7.4 mmHg SBP and 5.3 
mmHg DBP.  Hypertension was reported as an AE in 8 patients receiving AZD6244.  
An additional 8 patients from studies D1532C0008, D1532C0011, and D1532C0012 
reported AEs of hypertension.  In D1532C00005 small increases in SBP and DBP 
were observed consistently in the first week of treatment and hypertension was 
reported as an AE in 14.3% of patients.  Hypertension AEs in these studies were 
generally CTCAE grade 1 or 2 but resulted in initiation of antihypertensive 
medications in some patients. 
 
Adverse events relating to visual function have been reported at a low frequency in all 
studies.  There were no specific treatment emergent structural findings reported from 
those patients that underwent an ophthamological evaluation after reporting a visual 
disturbance adverse event. There were anecdotal reports of asymptomatic raised intra-
ocular pressure at the protocol mandated Week 4 eye test in one study. The events 
were reported under a variety of terms with the most common being blurred vision 
but also including visual disturbance (red spots, uneven floor, intermittent shadows, 
dark spots in viewing area), photopsia, diplopia, and altered visual depth perception.  
The majority of visual AEs were CTCAE grade 1 in intensity.  One AE of visual 
disturbance in D1532C0005 was CTCAE grade 3 in intensity, starting on day 2 of 
treatment but resolved fully without intervention four days later.   
 
One of the patients on D1532C00020 with raised intraocular pressure went on to 
report CTCAE grade 2 blurred vision followed by an SAE of convulsion which 
occurred two days after insertion of a biliary stent.  CT and MRI scans gave a 
differential of Reversible Posterior Leukencephalopathy Syndrome (RPLS) in 
combination with preexisting vascular abnormalties.  No other cases of suspected 
RPLS have been reported with AZD6244. 
 
Increases in the serum liver transaminases, ALT and AST have been observed in 
clinical trials with AZD6244. Mean increases were observed within 1 week of 


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AZD6244 treatment and did not continue to rise beyond levels reached by the end of 
the first 4 weeks of treatment, except in patients at time points immediately prior to 
withdrawal due to disease progression. The majority of reported transaminase 
elevations either remained within normal limits or increased by no greater than 1 
CTCAE grade. In Study D1532C00005 an increase in ALP was observed. However, 
no significant trends have been observed for bilirubin in any study, with either 
formulation. Regular measurements of AST, ALT and other liver function parameters 
will continue to be monitored and the health care professionals involved in clinical 
studies should look for signs of liver toxicity in patients receiving AZD6244. All 
patients with an aspartate aminotransferase (AST, SGOT), alanine aminotransferase 
(ALT, SGPT) or bilirubin value above upper limit of normal at the time of the last 
dose of AZD6244 should have a further liver chemistry profile (AST, ALT, bilirubin 
and alkaline phosphatase) performed 30 days after permanent discontinuation of 
AZD6244 in order to fully document reversibility. 
 
In the melanoma Phase II study (D1532C00003) an increase in serum phosphate was 
observed in some patients after initiation of AZD6244 when compared with patients 
randomized to temozolomide. One patient on AZD6244 required therapeutic 
intervention initiated due to a calcium:phosphate product which exceeded 4.5 
mmol/L. Regular monitoring of serum calcium and phosphorus levels, and the 
calcium:phosphate product is advised in clinical studies with AZD6244. 
 
In Study D1532C00005, data shows a slight decrease in platelet count, however this 
was not considered clinically significant. No other clinically significant changes in 
hematological parameters were identified across the clinical study program. However, 
hematological events are potential risks, particularly when AZD6244 is administered 
in combination with other anti-cancer therapies. 
 
2.1.2.3  Clinical Activity 
 
The following discussion summarizes the single agent efficacy data.  There is no 
efficacy data for the combination of AZD6244 and capecitabine 
 
ARRY-0101 was a Phase I, open-label, multicenter study was designed primarily to 
investigate the safety and tolerability of the free-base suspension formulation of 
AZD6244.  Objective tumor response evaluation using RECIST criteria indicate that 
the best overall response in this study was stable disease. Of the patients who had at 
least one pre- and postdose measurement of target lesions recorded, stable disease 
was observed in 17 patients. Long term (≥5 months) stable disease was observed in 
9/57 patients, 6 of whom had melanoma. 
 
Study D1532C00003, a Phase II, open-label, randomized study assessed the safety 
and efficacy of AZD6244 vs temozolomide (TMZ) in patients with unresectable 
AJCC stage 3 or 4 malignant melanoma in 200 randomized patients (104 for 
AZD6244 and 96 for TMZ).(14) In the overall population there was no statistically 
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and OS may have been improved in the TMZ treatment arm compared to those 
treated with AZD6244.  These data may be confounded by the high frequency of 
patients crossing-over from TMZ to AZD6244 in this study. Six patients receiving 
AZD6244 had a confirmed partial response (PR), of which 5 were BRAF+. Eleven 
patients randomized to TMZ had a confirmed response (10 PRs and 1 complete 
response [CR]), 3 of which (all PRs) were BRAF+.  
 
Study D1532C00008, a Phase II, open-label, randomized study assessed the efficacy 
and safety of AZD6244 vs capecitabine in 70 patients (38 for AZD6244 and 32 for 
capecitabine) with advanced or metastatic pancreatic cancer who had failed first-line 
gemcitabine therapy. There was no statistically significant difference between the 2 
treatment groups for the primary endpoint of time to death (TTD).  The median TTD 
was 164 days and 152 days in the AZD6244 and capecitabine groups, respectively. 
Results were similar for the secondary outcome variable of progression event 
count. Five patients (2 patients in the AZD6244 group and 3 patients in the 
capecitabine group) achieved a best overall response of PR, as defined by the 
investigator (unconfirmed).  Because tumor response was not an endpoint of the study 
and a single assessment of PR was accepted as a best overall response of PR, these 
are not considered robust data for response. 
 
Study D1532C0001 was a Phase II, open label, randomized study that assessed the 
efficacy and safety of AZD6244 versus capecitabine in 69 patients.(15) There was no 
significant difference between treatments in the primary endpoint of the number of 
patients with a disease progression event (82% patients in the AZD6244 group versus 
80% patients in the capecitabine group).  There was no evidence of a statistically 
significant difference in PFS between the groups. Overall best response by RECIST 
criteria was stable disease (10 patients) for AZD6244 while there was 1 patient with 
PR and 15 with stable disease in the capecitabine group).  
 
Study D1532C00012 was a Phase II, open-label, randomized study that assessed the 
efficacy and safety of AZD6244 versus pemetrexed in 84 patients (40 for AZD6244 
and 44 for pemetrexed) with NSCLC who had failed one or two prior 
chemotherapeutic regimens.(16)   The primary objective of this study was to assess 
the efficacy of AZD6244 versus pemetrexed in the second or third line treatment of 
advanced NSCLC.  There was no statistically significant difference between 
treatments in the primary endpoint of the number of patients with a disease 
progression event: 28 (70%) patients in the AZD6244 group versus 26 (59%) patients 
in the pemetrexed group. There was no difference in PFS between treatment groups. 
At the time of the final analysis, four patients had achieved a best overall response of 
CR (1 patient in the pemetrexed group) or PR (2 patients in the AZD6244 group, 1 
patient in the pemetrexed group) to treatment. 
 
Study D1532C0005 was a Phase I, open label, multi-center study to assess the safety, 
tolerability and pharmacokinetics of a capsule formulation of AZD6244 in patients 
with advanced solid malignancies who have failed standard therapy or for which no 
standard therapy exists.(17) Efficacy assessment in this study was an exploratory 


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endpoint.  Part A of the study (31 patients) was a dose escalation study designed to 
provide adequate tolerability, safety, pharmacokinetic, and pharmacodynamic data. In 
Part A, the doses investigated were 25 mg, 50 mg, 75 mg and 100 mg delivered twice 
daily. Part B (29 patients randomized) was designed to determine the relative oral 
bioavailability of the Hyd-Sulfate capsule and to expand the safety, tolerability and 
preliminary efficacy profile of the MTD from Part A (75 mg BID). In Part B, patients 
received either a single dose of capsule formulation or free-base suspension 
formulation on Day 1 and 8, followed by continuous twice daily dosing of capsule 
formulation from Day 9 onwards. Fifty-five patients had RECIST evaluable tumors. 
There was one complete response in the 75 mg dose cohort in Part A after 16 weeks. 
This patient had a BRAF+ melanoma. At the75 mg dose 16/35 (45.7%) patients had 
stable disease for ≥6 weeks. Nine patients in Part A and 13 patients in Part B had a 
best response of stable disease. Ten out of 55 (18.2%) patients (not including the 
patient who had a CR) had stable disease of ≥16 weeks. Seven patients in Part A and 
12 patients in Part B had a best response of progressive disease, and 10 patients in 
Part A and 3 patients in Part B were not evaluable for response.  
 
In summary, the results of four Phase II clinical studies with the free base suspension 
formulation as monotherapy compared to standard chemotherapy agents did not 
demonstrate superior efficacy of either agent. Objective responses were seen in both 
the melanoma and NSCLC studies. In the melanoma study D1532C00003, 5/6 of the 
partial responses were in patients with the BRAF mutation, and in addition a durable 
complete response has been seen in study D1532C00005 with the Hyd-Sulfate 
capsule formulation in a patient with BRAF+ melanoma. In the NSCLC phase II 
monotherapy study no tumor samples were available for either patient who 
experienced a partial response. 
 
2.1.2.4  Pharmacodynamics 
The effect of AZD6244 on the phosphorylation of ERK in peripheral blood 
mononuclear cells was evaluated in Part A of study ARRY-0401.  Using FACS 
analysis, the magnitude of ERK phosphorylation relative to baseline was determined 
in TPA-stimulated pre- and post-treatment blood samples.  AZD6244 inhibited TPA-
induced ERK phosphorylation at an IC50 of approximately 134 ng/mL (total 
concentration in plasma).  The magnitude of inhibition was found to correlate with 
plasma AZD6244 concentrations.  Further analyses using the active metabolite will 
be carried out in the future. 
 
Preliminary, unvalidated data from paired tumor biopsies pre- and post-dose (4 hours 
post-dose on ~ Day 15) were obtained from patients in Part B.  Formalin-fixed, 
paraffin embedded tissue samples were evaluated by immunohistochemistry for 
phosphorylated extracellular signal-regulated kinase - pERK (score range 0-400), 
proliferative index - Ki-67 (range 0-100%) and apoptosis by cleaved caspase 3 (0-
100%).  Evaluable pre and post biopsies were obtained from a range of tumors for 
Ki67 (20 patients), pERK (19 patients) and cleaved caspase 3 (16 patients).  Two 
patients were dosed at 200mg, the remaining at 100mg.  At the tolerated dose of 100 
mg, tumor pERK staining was reduced compared to untreated specimens, with a g-


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mean reduction in nuclear staining of 81% (90% CI 50% to 93%) compared to pre-
dose.  A reduction in Ki-67 was seen in 9/20 patients with a reduction greater than or 
equal to 50% of pre-dose seen in 5/20 patients.  No increases greater than 1% were 
seen on the apoptotic marker cleaved caspase 3. 
 
2.1.2.5  Potential Drug Interactions 
In vitro metabolic studies of AZD6244 using hepatocytes from humans and animals 
found that the biologically active N-desmethyl derivative was detected in mouse and 
human hepatocytes, was detected minimally in monkeys; and was not detected in rats 
(Investigator's Brochure, 2006).  Cytochrome P450 (CYP) 1A2 was the enzyme 
primarily responsible for the formation of the N-desmethyl derivative; CYP2C19 and 
CYP3A4 were also minimally involved in the transformation.  Neither AZD6244 nor 
its active metabolite were found to be inhibitors of CYP isoforms 1A2, 2C8, 2C19, 
2D6, or 3A4.  However, AZD6244 was found to be a weak inhibitor of CYP2C9 
(IC50 = 44.7 uM) and the N-desmethyl derivative was a weak inhibitor of CYP1A2 
(IC50 = 18.9 uM).  Thus, at the systemic AZD6244 concentrations observed following 
100mg AZD6244 mix and drink formulation in man, no significant cytochrome P450 
interactions would be expected.  Since the formation of N-desmethyl AZD6244 from 
AZD6244 may occur through the CYP 1A2 pathway and smoking induces this 
pathway, the smoking status of the subjects should be recorded in all studies (i.e., 
smoker or non-smoker) to investigate whether smoking status influences systemic 
drug exposures of N-desmethyl AZD6244. 
 
2.2  Other Agent(s) 
Capecitabine and radiation are frequently combined for the treatment of gastrointestinal 
malignancies.  Capecitabine is a fluoropyrimidine carbamate that is an orally administered 
prodrug of 5’-deoxy-5-fluorouridine (5’-DFUR) that is converted to 5-fluorouracil (5-FU).  
5’-DFUR is hydrolyzed to the active drug 5-FU by thymidine phosphorylase which is present 
in many tissues in the body.  Thymidine phosphorylase is expressed in higher concentrations 
in some human carcinomas compared to surrounding tissues. 
 
In the setting of rectal cancer, there is a growing experience of Capecitabine and radiotherapy 
in the neoadjuvant setting.(18)  The maximum tolerated dose of Capecitabine is 800-825 
mg/m2 twice daily combined with 50.4 Gy of radiation.(19-22)  Downstaging occurs in 
approximately 50-85% of patients receiving the combination of Capecitabine and radiation in 
the neoadjuvant setting for locally advanced rectal cancer.  Pathologic complete response 
rates of 8-16% have been described with the combination, similar to that observed with the 
combination of 5-FU and radiation in this setting.(23, 24)  The most common Grade 3 or 
higher toxicity observed with Capecitabine in this setting is diarrhea which may be observed 
in as many as 20% of patients. 
 
2.3  Locally Advanced Adenocarcinoma of the Rectum 
Over 40,000 cases of adenocarcinoma of the rectum occurred in the United States in 
2008.(25)  Patients with locoregionally advanced disease (T3, T4, and N positive) are at a 
high risk of local recurrence if treated with surgery alone.  Combined modality therapy with 


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chemotherapy and radiation improve survival and local control after surgical resection of 
locally advanced rectal cancer.(26-28)  Treatment of rectal cancer with chemotherapy and 
radiation in a neoadjuvant setting further improves local control and reduces toxicity 
compared to adjuvant chemoradiation.(23)  Currently, the standard of care in the United 
States for patients with locally advanced (T3-T4N0, N+) rectal cancer is combined 
chemoradiation followed by surgical resection with additional adjuvant chemotherapy 
based on stage and risk factors.  Because local recurrences are morbid and difficult to 
manage effectively, radiation is being evaluated with new agents delivered alone or with 
additional adjuvant therapy to improve outcomes and reduce toxicity.  
 
2.4  Rationale 
Colorectal cancers frequently harbor a common set of well-described genetic abnormalities.  
For example, in clinical colorectal cancer specimens, the prevalence of RAS mutations is 
40%,(29) the prevalence of EGF/EGFR over-expression is 44%,(30) and the prevalence of 
BRAF mutations is approximately 14%.(31)  The high prevalence of mutations resulting in 
activation of the mitogen-activated protein kinase (MAPK) cascade via activating Ras 
mutations in addition to the prevalence of pathway activation through autocrine and 
paracrine mechanisms (i.e. EGF/EGFR) presents a unique therapeutic target.  The 
availability of novel small molecule inhibitors to elements of the MAPK signal transduction 
pathway provides an opportunity to target Ras oncogene addition and EGFR pathway 
addiction as a therapeutic intervention. 
 
In addition, the Ras-MAPK pathway is of particular interest in the context of radiotherapy 
for a number of reasons.  Activation of the Raf-MEK-ERK pathway occurs rapidly in tumor 
cells after exposure to ionizing radiation. (32-34)  Activation of the Ras-Raf-MEK-ERK 
cascade though mutations in Ras and Raf is known to result in enhanced tumor cell 
proliferation and enhanced survival after irradiation. (35-37)  Furthermore, inhibition of 
Ras and Raf in cell lines with activating Ras mutations results in sensitization to ionizing 
radiation. (37-39)  These data suggest that inhibition of the Ras-Raf-MEK-ERK cascade 
may sensitize cells to ionizing radiation. 
 
Preclinical work in the Radiation Oncology Branch at the NCI has shown that AZD6244 
enhances radiation induced cell death and regrowth delay in a variety of cell lines both in 
vitro and in vivo. (40)   For in vivo studies, AZD6244 was delivered to groups of 5 to 8 
tumor bearing nude mice by oral gavage four hours prior to irradiation with a single 
fraction of 3 Gy (Figure 1).  Mice were followed individually and tumor volumes were 
measured at least twice weekly.  To obtain a dose enhancement factor comparing the tumor 
radiation response in mice with and without AZD6244 treatment, the normalized tumor 
growth delays were calculated, which accounts for the contribution of AZD6244 to tumor 
growth delay induced by the combination treatment.  Normalized tumor growth delay was 
defined as the time in days for tumors to grow from 172 to 1,500 mm3 in mice exposed to 
the combined modality minus the time in days for tumors to grow from 172 to 1,500 mm3 
in mice treated with AZD6244 only.  The dose enhancement factor, obtained by dividing 
the normalized tumor growth delay in mice treated with AZD6244 + IR by the absolute 
growth delay in mice with A549 tumors treated with radiation only, was 3.38 for 50 mg/kg 
of AZD6244.  The dose enhancement factor for the addition of AZD6244 in the MiaPaCa2 


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xenograft model was 2.3.   
 
 
Figure 1.  The effects of AZD6244 on A549 and MiaPaCa2 xenograft tumors.   When tumors reached 
177 mm3 in size, mice were randomized into four groups: vehicle, AZD6244, radiation, or AZD6244 plus 
radiation. AZD6244 was dissolved in water and given by oral gavage at 50 mg/kg delivered in a single 
dose. Radiation (3 Gy) was delivered 4 hours after the AZD6244 treatment. Each treated group contained 5 
mice with the vehicle control group containing 10 mice.  From Chung et al.(40) 
 
Further preclinical work has shown that AZD6244 abrogates the G2 cell cycle checkpoint 
and enhances mitotic catastrophe following ionizing radiation.(40)  In addition, no 
enhancement of radiation response was seen in fibroblast cell lines (Figure 2, unpublished 
data) suggesting that AZD6244 may selectively sensitize tumor cells to radiation. 


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Figure 2.  The effects of AZD6244 on the radiation response of MRC5 fibroblasts.    MRC5 cells 
(human fibroblast) were plated at appropriate dilutions and treated with AZD6244 (250 nM) or vehicle 
control.  Cells were then exposed to graded doses of radiation and incubated for 10 to 14 days before 
counting of colonies. 
 
Recently, the effects of AZD6244 as a radiation modifier were extended to human 
colorectal carcinoma and lung xenografts.(41)  We have recently extended our in vitro 
observations of enhanced radiation response with AZD6244 to the setting of 
chemoradiotherapy with 5-FU.  We have found additional sensitization when 5-FU is added 
to AZD6244 in the setting of radiation suggesting a lack of interference with 5-FU.  In 
addition, we found no evidence of a negative interaction between AZD6244 and 5-FU 
(Figure 3, unpublished data), an important consideration when considering the systemic 
therapeutic effects of Capecitabine.  Additional work exploring the interaction of 5-FU and 
AZD6244 has shown that exposure to AZD6244 and 5-FU does not result in antagonism in 
vitro regardless of sequencing (unpublished data, data not shown). 


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Figure 3.    Effects of AZD6244 on HCT 116 and HT29 cells.  HT29 (A) and HCT116 (B) cells were 
plated at appropriate dilutions and treated with the indicated concentration of 5-fluorouracil (16 hour 
exposure prior to RT), AZD6244 (1 hour prior to RT), both AZD6244 and 5-FU, or vehicle control.  Cells 
were then exposed to graded doses of radiation and incubated for 10 to 14 days before counting of colonies.  
After a similar treatment with no radiation, cells were incubated for 48 hours and an MTT assay was 
performed to assess proliferation in HT29 (C) and HCT116 (D) cells (5FU before AZD).  A second set of 
MTT assays was performed to verify that treatment with AZD6244 prior to 5FU did not result in 
antagonism (AZD before 5FU). 
 
We have demonstrated that inhibition of AZD6244 sensitizes to radiation induced tumor cell 
death via abrogation of the G2 checkpoint and an increase in mitotic catastrophe.  Given the 
importance of signal transduction in radiation pro-survival mechanisms and the role of 
radiation in the standard management of locally advanced adenocarcinoma of the rectum, the 
addition of AZD6244 to radiation and Capecitabine is of interest. 


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2.5 Correlative Studies Background 
The laboratory correlates will be performed with exploratory intent, using primarily 
descriptive techniques.  Two classes of markers will be studied in blood and tumor tissues:  
1) proteins expected to have altered phosphorylation or expression with AZD6244 treatment 
and 2) mutations that may predict for AZD6244 efficacy.  Tumor tissue will be sampled prior 
to treatment, after a one week lead in phase of AZD6244 (day 8), and after one week of 
AZD6244 in combination with Capecitabine and radiation (day 15).  Blood will be sampled 
for correlative studies prior to treatment, after a 7 day lead in phase of AZD6244, after one 
week of AZD6244 in combination with Capecitabine and radiation, and at one month 
following completion of all treatment.  The markers that will be evaluated in blood include 
phosphorylation of ERK in peripheral blood mononuclear cells and levels of plasma TGFα.   
 
2.5.1 Evaluation of mutations in KRAS, BRAF, and PTEN in tumor tissue. 
Activating mutations in KRAS and BRAF are thought to predict for single agent efficacy 
with MEK inhibition(42) and may also be implicated in radiation response with 
AZD6244.  This will be an exploratory endpoint for this study as the number of patients 
included are small and we estimate that only 40% of participants will have activating 
mutations.  PTEN status may predict for resistance to MEK inhibition.(43)  We 
hypothesize that the presence of activation mutations in KRAS or BRAF will be positively 
correlated with pathologic CR rate while loss of PTEN will be negatively correlated with 
pathologic CR.  The presence of activating mutations will be evaluated via DNA 
purification, amplification via polymerase chain reaction, and sequencing.  For KRAS, 
codons 12 and 13 will be amplified.  For BRAF, exon 15 will be amplified.  This analysis 
will be performed on pretreatment specimens only.  These assays will be performed by 
the laboratory of pathology, NCI.  If sufficient additional tissue or DNA remains, PTEN 
exon 1-9 amplification will be completed in the laboratory of Dr. Deborah Citrin 
followed by sequencing.  This will be completed for tumors in which PTEN expression is 
not detected by immunohistochemistry. 
 
2.5.2 Evaluation of tumor ERK phosphorylation and PTEN expression 
ERK is the immediate downstream target of MEK and may be phosphorylated at baseline 
or after radiation.  Comparisons of pre and post treatment changes with 
immunohistochemistry may provide direct evidence of AZD6244 effect in tumors.  In 
addition, tumor ERK phosphorylation has not yet been correlated to PBMC ERK 
phosphorylation in humans.  To provide evidence that PBMC ERK phosphorylation is an 
accurate surrogate for tumor ERK phosphorylation, we plan to evaluate these markers in 
the patients enrolled on this trial at three time points:  1) prior to treatment, 2) after a one 
week lead in of AZD6244, and 3) after one week of combined AZD6244, Capecitabine, 
and radiation.  We have shown that radiation and 5-FU as single agents or in combination 
induce ERK phosphorylation in colorectal cell lines (Figure 4).  We hypothesize that 
treatment with AZD6244 will result in reduced ERK phosphorylation in PBMC and 
tumor tissue after single agent treatment with AZD6244 and after combined treatment. 
 


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Figure 4.  Effects of AZD6244 on ERK phosphorylation after treatment with radiation (RT), 5-FU, 
and/or AZD6244.  Cells were plated and treated with AZD6244, 5-FU, and RT at the doses indicated in a 
fashion identical to that performed for clonogenic assays.  Cells were harvested and subjected to western 
blotting two hours after IR. 
 
If sufficient tissue is available, additional staining for PTEN expression will be 
performed on initial biopsies.  In tumors with absent PTEN expression, the presence of 
PTEN mutations will be assessed.  PTEN status may predict for resistance to MEK 
inhibition.(43)   
 
 
2.5.3 Evaluation of PBMC ERK phosphorylation 
The ability to detect changes in PBMC following treatment with AZD6244 has been 
demonstrated in Phase I trials (ARRY-0401), however this has not to our knowledge been 
correlated to tumor biopsies.  We hope to determine if a correlation exists between 
alterations in circulating lymphocyte pERK and tumor pERK during AZD6244 treatment.  
Whole blood will be collected at the same time points as tumor biopsies:  1) prior to 
treatment, 2) after a one week lead in of AZD6244, and 3) after one week of combined 
AZD6244, Capecitabine, and radiation.  ERK phosphorylation will also be obtained at 
the times of pharmacokinetic (PK) sampling on day 4 or 5 and day 11 or 12.  See section 
2.5.5 for a discussion of PK sampling time points and analysis. 
 
2.5.4 Evaluation of plasma TGF alpha 
Data generated in our laboratory supports that the radiation sensitizing effects of 
AZD6244 are in part related to a reduction in TGFα secretion with AZD6244 treatment. 
TGFα is secreted after radiation and is thought to act as a survival factor through 
EGFR-Akt signaling.  We have shown that AZD6244 treatment reduces TGFα secretion 
at baseline and after irradiation (figure 5, unpublished data). 
 
250nM AZD6244 
No RT 
15uM 5FU 
+ 
- 
+ 
- 
- 
- 
+ 
+ 
6 Gy 2 hr 
+ 
- 
+ 
- 
- 
- 
+ 
+ 
HCT116 
α-Erk 1/2 
α-pErk 1/2 
α-actin 


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Figure 5.  The effects of AZD6244 on radiation induced TGF-α secretion in A549 cells.  A549 cells 
were exposed to AZD6244 (250 nM) or vehicle control for 16 hours, irradiated, and incubated until the 
time points shown.  Media was collected and subjected to ELISA for soluble TGF-α.  TGF-α secretion was 
induced by irradiation in a time dependent fashion.  Basal and radiation-induced TGF-α secretion was 
dramatically reduced with AZD6244 treatment. 
 
We have also shown that inhibition of TGFα with a blocking antibody sensitizes A549 
cells to radiation (unpublished data).  Supplementation of TGFα in the media of cells 
treated with AZD6244 resulted in a reduction in radiation sensitization and a reduction 
in the number of cells undergoing mitotic catastrophe (figure 6, unpublished data).  
These results suggest that TGFα is a survival factor after radiation that is reduced with 
AZD6244.  Therefore, a comparison of baseline and post-treatment TGFα may provide 
a marker of radiation sensitization with AZD6244.   
 
 
Figure 6.  The effects of TGF-α on cell survival after irradiation and treatment with AZD6244. A) A549 
cells were exposed to AZD6244 (250 nM) or vehicle control for 16 hours, and irradiated with graded doses of 
X-rays.  Recombinant human TGF-α (5 pg/ml) was supplemented in media at the time of irradiation. Colony-
forming efficiency was determined 14 days later and survival curves generated after normalizing for cell killing 
by AZD6244 alone.  There was no measurable increase or decrease in plating efficiency with the addition of 
recombinant human TGF-α in the absence of irradiation. The data represent the mean of three independent 


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experiments.  B) A549 cells growing in chamber slides were exposed to AZD6244 (250 nM) or vehicle control, 
irradiated (4 Gy), and fixed at the specified times evaluation of mitotic catastrophe. Nuclear fragmentation was 
evaluated in 150 cells per treatment per experiment.  Nuclear fragmentation was defined as the presence of two 
or more distinct lobes within a single cell. PE, plating efficiency with AZD6244; DEF, dose enhancement 
factor. Columns, mean; bars, SE.  Nuclear fragmentation was defined as the presence of two or more distinct 
lobes within a single cell. 
 
We have confirmed that changes in tumor levels of TGFα can be observed in tumors in  
vivo (Figure 7).  Plasma TGFα has been evaluated as a molecular marker of response in a 
recent clinical trial of chemoradiation with cetuximab for treatment of patients with rectal 
cancer.(44)  In this study TGFα was shown to be altered after treatment with cetuximab.  
We hypothesize that a reduction in TGFα will be observed in the plasma of patients 
treated with AZD6244.  The use of TGFα as a marker with MEK inhibition may prove 
more useful compared to EGFR inhibition (cetuximab) due to the high rate of Ras 
mutations in colorectal tumors.  The usefulness of TGFα levels for response to EGFR 
inhibition may be questionable because TGFα is induced by ERK phosphorylation which 
should be constitutively activated in the setting of Ras mutations, regardless of the 
activation status of the EGF receptor.  Because MEK, the target of AZD6244 is 
downstream of Ras, it is possible that TGFα will be a much more informative marker in 
the setting of Ras mutations. 
 
Figure 7.  The effects of AZD6244 and radiation on TGF alpha levels in A549 xenografts. 
When flank A549 xenograft tumors reached 177 mm3 in size, mice were randomized into four 
groups: vehicle, AZD6244, radiation, or AZD6244 plus radiation. AZD6244 was dissolved in 
water and given by oral gavage at 50 mg/kg delivered in a single dose. Radiation (3 Gy) was 
delivered 4 hours after the AZD6244 treatment. Each treated group contained 3 mice. Tumors 
were harvested at the time points shown and homogenized.  Lysates were subjected to ELISA for 
soluble TGF-α and values were normalized to tumor weight.  TGF-α levels were induced by 
irradiation and reduced with AZD6244 treatment.  AZD:  AZD6244.  Columns, mean; bars, SE 
 
2.5.5 Pharmakokinetic Measurements 
Blood samples (2 ml) for the determination of plasma AZD6244, N-desmethyl AZD6244 
and AZD6244 Amide determination will be collected from patients in a comprehensive 
PK sampling schedule.  Blood will be immediately placed on ice and the specimen 
transported to the laboratory of Deborah Citrin for processing and storage.  Analysis of 
plasma samples for the determination of AZD6244, N-desmethyl AZD6244 and 
AZD6244 Amide concentrations will be the responsibility of the Clinical Pharmacology 


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& DMPK(Drug Metabolism and Pharmacokinetics) Department, Alderley Park, 
AstraZeneca, UK.  Specimens will be shipped in batches from Dr. Deborah Citrin’s 
laboratory to Astra Zeneca’s contract laboratory for analysis. 
 
For once daily dosing (dose level -1) 
• Day 4 or 5 (AZD6244 alone): Pre-dose (within 10 minutes of dosing), 30 minutes, 
1 hour, 1 hour 30 minutes, 2, 4, 8, 12 and 24 hours post-dose (24 hour sample is 
pre- the next day’s dose).   
• Day 11 or 12 (AZD6244 + capecitabine + radiotherapy): Pre-dose (within 10 
minutes of dosing), 30 minutes, 1 hour, 1 hour 30 minutes, 2, 4, 8, 12 and 24 
hours post-dose (24 hour sample is pre- the next day’s dose). 
For twice daily dosing (dose levels 1 and 2): 
• Day 4 or 5 (AZD6244 alone): Pre-dose (within 10 minutes of dosing), 30 minutes, 
1 hour, 1 hour 30 minutes, 2, 4, 8 and 12 hours post-dose (12 hour sample is pre- 
the next day’s dose). 
• Day 11 or 12 (AZD6244 + capecitabine + radiotherapy): Pre-dose (within 10 
minutes of dosing), 30 minutes, 1 hour, 1 hour 30 minutes, 2, 4, 8 and 12 hours 
post-dose (12 hour sample is pre- the next day’s dose). 
 
The actual sample time and date of all PK samples will be recorded. 
 
 
3. PATIENT SELECTION 
 
3.1  
Eligibility Criteria  
 
3.1.1 Patients must have histologically or cytologically confirmed locally advanced, 
non-metastatic adenocarcinoma of the rectum (clinical stage T3 anyN, T4 anyN, or 
AnyT N+). 
 
3.1.2 Patients with recurrent adenocarcinoma of the rectum with no clinically evident 
distant disease will be eligible if they are deemed to have pelvic nodal metastases or 
disease extending through the muscularis of the rectum.  These patients should be 
evaluated by a Radiation Oncologist, Medical Oncologist and Surgeon prior to 
enrolling on study to confirm anticipated resectability.  These patients should not 
have received prior radiotherapy for management of their rectal cancer. 
 
3.1.3 Age >18 years. 
 
3.1.4 ECOG performance status <1 (Karnofsky >70%, see Appendix A). 
 
3.1.5 Patients must have normal organ and marrow function as defined below: 
 
− 
leukocytes  
 
 
 
 
>3,000/mcL 
− 
absolute neutrophil count  
>1,500/mcL 
− 
platelets:  
 
 
 
 
>100,000/mcL 


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− 
total bilirubin:   
 
 
 
within normal institutional limits except for  
 
 
 
 
 
 
 
 
patients with Gilbert’s who must have a  
 
 
 
 
 
 
 
 
direct bilirubin < 1.0 mg/dL 
− 
AST(SGOT)/ALT(SGPT) 
<2.5 X institutional upper limit of normal 
− 
creatinine  
 
 
 
 
within normal institutional limits 
 
OR 
− 
creatinine clearance  
 
>60 mL/min/1.73 m2 for patients with creatinine 
levels above institutional normal.  
 
3.1.6 Women of child-bearing potential and men must agree to use adequate 
contraception (hormonal or barrier method of birth control; abstinence) prior to study 
entry, for the duration of study participation, and for six months after the completion 
of radiation.  Women of child-bearing potential must have a negative pregnancy test 
prior to entry.  Should a woman become pregnant or suspect she is pregnant while 
participating in this study, she should inform her treating physician immediately.  
Adequate contraception for male patients should be used for 6 months after 
irradiation. 
 
3.1.7 Ability to understand and the willingness to sign a written informed consent 
document. 
 
3.1.8    Willingness to sign a release of medical records pertaining to previous and future 
treatment for rectal cancer. 
 
3.2  
Exclusion Criteria 
 
3.2.1 Chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or 
mitomycin C) prior to entering the study or lack of recovery from adverse events due 
to agents administered more than 4 weeks earlier. 
 
3.2.2 Patients may not be receiving any other investigational agents. 
 
3.2.3 History of allergic reactions attributed to compounds of similar chemical or 
biologic composition to AZD6244 or other agents used in study. 
 
3.2.4 Previous MEK inhibitor use.  
 
3.2.5 Contraindications to radiotherapy to the pelvis such as inflammatory bowel 
disease or known genetic sensitivity to ionizing radiation such as ataxia 
telengiectasia. 
 
3.2.6 Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that would limit compliance with 
study requirements. 
 


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3.2.7 Patients with QTc interval >470 msecs or other factors that increase the risk of 
QT prolongation or arrhythmic events (e.g., heart failure, uncorrectable hypokalemia, 
family history of long QT interval syndrome) including heart failure that meets New 
York Heart Association (NYHA) class III and IV definitions (see Appendix B) are 
excluded. 
 
3.2.8 Required use of a concomitant medication that can prolong the QT interval.  See 
Appendix C for a table of medications with the potential to prolong the QTc interval.  
A comprehensive list of agents with the potential to cause QTc prolongation can be 
found at http://www.arizonacert.org/medical-pros/drug-lists/drug-lists.htm. 
 
3.2.9 Refractory nausea and vomiting, chronic gastrointestinal diseases (e.g. 
inflammatory bowel disease), or significant bowel resection that would preclude 
adequate absorption. 
 
3.2.10 HIV-positive patients on combination antiretroviral therapy. 
 
3.2.11  Known dihydropyrimidine dehydrogenase deficiency. 
 
3.2.12  History of prior radiation to the pelvis 
 
3.2.13  For patients with newly diagnosed rectal cancer, prior therapy for 
adenocarcinoma of the rectum with the exception of diverting colostomy if required 
to relieve obstruction (including chemotherapy). 
 
3.2.14. Patients with recurrent rectal cancer may not have undergone prior radiotherapy 
for rectal adenocarcinoma or have received therapy for the recurrence with the 
exception of diverting colostomy if required to relieve obstruction. 
 
3.2.15  History of myocardial infarction within the past 6 months or history of ventricular 
arrhythmia 
 
3.2.16  Uncontrolled hypertension 
 
3.2.17  Pregnant or lactating females are excluded 
 
3.3 
Research Eligibility Evaluation 
All referred patients who meet the eligibility criteria will be evaluated in the Radiation 
Oncology Clinic at the National Cancer Institute.  All screening studies will be performed 
within 14 days of protocol enrollment unless otherwise stated. 
3.3.1  Clinical evaluation including documentation of performance status, medications 
and prior history of radiation, including smoking history 
• EKG for determination of QTc 
• Total colonoscopy within 8 weeks of onset of study when possible. This may 
be performed at an outside institution as long as the report is available for 


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review. 
• Pulse oximetry 
• Echocardiogram or MUGA 
 
3.3.2  Radiographic studies: 
• CT (chest, abdomen and pelvis) to confirm the absence of metastases will be 
reviewed to confirm the presence of resectable disease within 4 weeks of 
onset of study (outside studies may be used if acquired in the appropriate 
timeframe).  
• Transrectal ultrasound or MRI of the pelvis to stage primary or locally 
recurrent rectal tumor within 4 weeks of onset of study (outside studies may 
be used if acquired in the appropriate timeframe).  
 
3.3.3  Laboratory studies:   
• Serum creatinine, Serum hepatic panel, complete blood count with 
differential, APTT, PT. Urine pregnancy test for women of childbearing 
potential, serum CEA level 
 
3.3.4  Pathologic assessment:   
• A copy of path report along with slides and blocks of biopsy material for 
review by NCI Surgical Pathology. 
 
3.3.5  Surgical consultation: 
• NIH surgical consultation will be obtained for all patients. 
 
3.4   
Registration Procedures 
Authorized staff must register an eligible candidate with the NCI Central Registration Office 
(CRO) within 24 hours of signing consent. A registration Eligibility Checklist from the Web 
site (http://camp.nci.nih.gov/ccr/welcome.htm) must be completed and faxed to (301) 480-
0757. After confirmation of eligibility at Central Registration Office, CRO staff will call 
pharmacy to advise them of the acceptance of the patient on the protocol prior to the release 
of any investigational agents. Verification of Registration will be forwarded electronically 
via e-mail. Please note that it is very important for all registrars to acquire encrypted e-mail 
from the NIH Help Desk since the verification of registration includes patient information. A 
recorder is available during non-working hours. 
 
 
4. TREATMENT PLAN 
 
4.1  
Protocol Therapy Administration 
4.1.1  AZD6244 administration 
Treatment will be administered on an outpatient basis.  Reported adverse events and potential 
risks for AZD6244, radiation, and Capecitabine are described in Section 6.  Appropriate dose 
modifications for AZD6244 and Capecitabine are described in Section 5.  No investigational or 
commercial agents or therapies other than those described below may be administered with the 
intent to treat the patient's malignancy. 


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Dose Escalation Schedule 
Dose Level 
Dose 
 
AZD6244 
 
Capecitabine 
 
Radiation* 
 
Level -1 
 
50 mg PO QD 
Weeks 1-7 
 
825 mg/m2 PO every 
12 hours 
Weeks 2-7 
 
5040 cGy 
Weeks 2-7 
 
Level 1 
 
50 mg PO BID 
Weeks 1-7 
 
825 mg/m2 PO e 
every 12 hours 
Weeks 2-7 
 
5040 cGy 
Weeks 2-7 
 
Level 2 
 
75 mg PO BID 
Weeks 1-7 
 
825 mg/m2 PO every 
12 hours 
Weeks 2-7 
 
5040 cGy 
Weeks 2-7 
* An additional 360 cGy may be delivered for fixed T4 tumors for a total dose of 5400 cGy 
 
Dose-escalation of AZD6244 will begin at dose level 1, 50 mg PO BID delivered 
continuously, 7 days per week beginning one week prior to the initiation of 
chemoradiotherapy and continuing until the last day of chemoradiotherapy.  Dose level -1 
will only be delivered if Dose Level 1 is considered to be not tolerated due to toxicity 
observed in dose level 1 patients. 
• Patients will be provided with a Medication Diary for AZD6244 (Appendix D), 
instructed in its use, and asked to bring the diary with them to each appointment.   
• Take AZD6244 capsules on an empty stomach (either 1 hour before or 2 hours after 
meals).  AZD6244 capsules should be taken with water only.  
• In the event of AZD6244 de-escalation to dose level -1 (50 mg PO QD), the 
patient will be instructed to take AZD6244 as a morning dose. 
• Follow up for certain adverse events (AEs) should be performed to better 
characterize the effects of AZD6244 therapy:  
• Patients experiencing edema should have cardiac ejection fraction (EF) 
measurements, electrocardiogram, serum chemistry (including electrolytes 
and albumin), and routine urinalysis. 
• Patients with symptoms consistent with cardiac impairment (e.g., 
congestive cardiac failure, edema, or dyspnea) should have EF 
measurements (MUGA scan or echocardiography) and electrocardiogram 
at the time of the event as well as other routine investigations. 
• Respiratory events (including dyspnea or pulmonary edema) should be 
followed up with an electrocardiogram, EF measurement, and chest X-ray. 
• Oxygen saturation will be measured at baseline and again following any 
respiratory event. 
• Patients experiencing visual disturbances should undergo a complete 
ophthalmologic examination, including a slit lamp examination. 
 
4.1.2 Capecitabine administration 


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Capecitabine will be administered at a dose of 825 mg/m2 PO every 12 hours delivered 
approximately two hours prior to radiotherapy and the second dose will be delivered 12 
hours later.  Doses will be rounded to the nearest 150 mg.  Patients will begin 
Capecitabine dosing on the first day of radiotherapy and will continue to receive 
Capecitabine on days of radiotherapy (Monday through Friday) until the final day of 
radiotherapy. Patients will be instructed to take Capecitabine with food. 
 
Administration with Warfarin can increase the INR beyond expected.  Capecitabine should 
not be administered with aluminum hydroxide or magnesium hydroxide containing antacids, 
such as Maalox, as it may increase the plasma concentrations of capecitabine and its 
metabolites.  
 
4.1.3 Radiotherapy administration 
4.1.3.1  Modality, Fractionation, and total dose   
Radiation will be delivered with external beam radiation with megavoltage radiation 
with beam energies of 6MV or higher.  Treatment will be delivered in 1.8 Gy 
fractions 5 days per week with every field treated each day.  The total dose to the 
PTV encompassing the pelvic lymph nodes and tumor will be 45 Gy in 25 fractions.  
A boost to the tumor will be delivered for an additional 5.4 Gy in 1.8 Gy fractions.  
Fixed T4 tumors may receive a boost of 9 Gy for a total dose of 54 Gy. 
 
4.1.3.2 Simulation 
Patients will be simulated supine or prone as appropriate to the clinical status and 
staging.  Simulation will be performed with a CT simulator in the Radiation 
Oncology Branch.  Oral contrast will be delivered approximately one hour prior to 
simulation to allow opacification of small bowel unless contraindicated.  Rectal 
contrast will be delivered just prior to simulation unless contraindicated.  An anal 
marker will be used at the time of simulation. 
 
4.1.3.3 Volume definitions  
Initial pelvic field:    The gross tumor volume (GTV) will be defined as all gross 
disease evident on imaging and examination.  The clinical target volume (CTV) will 
be defined as the combination of  
1)  the rectal GTV with a 2.5 cm craniocaudal margin and a 1.5 cm radial margin 
2) the nodal GTV with 1.5 cm margin 
3) the iliac vessels with 1 cm margin (including the external iliac vessels only if T4 
and invading anterior structures) extending craniocaudally to the L5/S1 interspace 
4) the presacral space from S1-S5 
5) the mesorectal and perirectal lymphatics.  The planning target volume will be 
defined as the CTV with a 5-7 mm margin.   
 
Boost field:  The boost field will include the gross tumor including involved lymph 
nodes with a 2.0 cm margin to CTV.  The boost field CTV must include the sacral 
hollow.  The PTV will be defined as CTV with 5 to 7 mm margin. 
 
4.1.3.4 Dose specification 


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The PTV doses should meet the following criteria: 
1) > 93% of the PTV should receive at least 93% of the prescribed dose 
2) < 5% of the PTV should receive more than 110% of the prescribed dose. Efforts 
will be made to reduce heterogeneity if possible. 
 
4.1.3.5 Normal structures 
Minor modifications to normal tissue dose constraints will be made if the total tumor dose is 
5400 cGy. Every effort will be made to minimize areas of non target tissue that receive 
target doses.  Specific attention will be paid to reducing exposure to small bowel, 
ileocecal region, femoral neck, bladder, and anal sphincter if uninvolved.  The 
following organs will be contoured for treatment planning purposes and will be 
evaluated with dose volume histograms:  bladder, femoral neck and head, small 
bowel. 
The following dose goals will apply for normal tissues: 
Small bowel:  No more than 180 cc above 35 Gy, No more than 100 cc above 40 Gy, 
No more than 65 cc above 45 Gy, No small bowel volume should receive 50 Gy 
Femoral heads: No more than 40% volume above 40 Gy, No more than 25% volume 
above 45 Gy, No femoral head volume should receive 50 Gy 
Bladder: No more than 40% volume above 40 Gy, No more than 15% volume above 
45 Gy, No bladder volume should receive 50 Gy 
 
4.1.4  Surgery 
Surgery is not part of this protocol.  It is anticipated that at the completion of 
chemoradiation patients will have a four to six week recovery period and will undergo 
surgical resection as is the current clinical standard. Surgical specimens will be reviewed 
by the Surgical Pathology laboratory at NIH for examination and determination of 
response. 
 
4.2  
Definition of Dose-Limiting Toxicity 
• Dose-limiting toxicities will be defined as follows (during treatment and within the 
first three weeks after treatment):  
1.  Recurring and persistent Grade 3 diarrhea despite appropriate medical therapy.  
2.  ANC <500 for more than 5 days or neutropenic fever  
3.  Grade 4 thrombocytopenia 
4.  Recurring and persistent Grade 3 nausea/vomiting despite appropriate anti-
emetic therapy 
5.  Grade 4 dermatitis acneiform rash 
6.  Grade 4 fatigue 
7.  All other non-hematologic toxicities of grade 3 or higher except electrolyte 
abnormalities that are correctable 
8.  Delays in radiation treatment due to toxicity of more than 2 weeks (cumulative 
duration over the course of the entire treatment). 
 
• Management and dose modifications associated with the above adverse events are 
outlined in Section 5. 
 


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• 
Dose escalation will proceed within each cohort according to the following scheme.  
Dose-limiting toxicity (DLT) is defined above.  
 
Number of Patients with DLT at a 
Given Dose Level 
Escalation Decision Rule 
0 out of 3 
Enter 3 patients at the next dose level. 
>2 
Dose escalation will be stopped.  This dose level will be 
declared the maximally administered dose (highest dose 
administered).  Three (3) additional patients will be 
entered at the next lowest dose level if only 3 patients were 
treated previously at that dose.  If >2 initial patients 
experience a DLT at dose level 1, de-escalation to dose 
level -1 will occur. 
1 out of 3 
Enter at least 3 more patients at this dose level. 
• If 0 of these 3 patients experience DLT, proceed to the 
next dose level. 
• If 1 or more of this group suffer DLT, then dose 
escalation is stopped, and this dose is declared the 
maximally administered dose.  Three (3) additional 
patients will be entered at the next lowest dose level if 
only 3 patients were treated previously at that dose. 
<1 out of 6 at highest dose level below 
the maximally administered dose 
This is generally the recommended phase 2 dose. At least 6 
patients must be entered at the recommended phase 2 dose. 
 
4.3 General Concomitant Medication and Supportive Care Guidelines 
Because there is a potential for interaction of AZD6244 and Capecitabine with other 
concomitantly administered drugs through the cytochrome P450 system, the case report form 
must capture the concurrent use of all other drugs, over-the-counter medications, or 
alternative therapies.  The Principal Investigator should be alerted if the patient is taking any 
agent known to affect or with the potential to affect selected CYP450 isoenzymes (2C9 and 
1A2). 
• Investigators should document the patient's comedications to investigate any 
potential drug interactions. 
• Because there is a potential for interaction of AZD6244 with other concomitantly 
administered drugs through the cytochrome P1A2 system, the case report form 
(CRF) must capture the concurrent use of all other drugs, over-the-counter 
medications, or alternative therapies.  Throughout the study, patients should avoid 
changes to, or the addition of all concomitant medications, in particular any that 
may affect the metabolism of AZD6244 (eg, CYP1A2 or 3A4 
inhibitors/inducers), unless considered clinically indicated.  If patients are taking 
strong inducers or inhibitors of CYP1A2 these medications will be discontinued 
prior to initiation of protocol therapy. 
• Because there is a potential for interaction of Capecitabine with other 
concomitantly administered drugs through the CYP2C9 system, the case report 
form (CRF) must capture the concurrent use of all other drugs, over-the-counter 


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medications, or alternative therapies. The Principal Investigator should be alerted 
if the patient is taking any agent known to affect or with the potential to interact 
with Capecitabine.  Patients will be transitioned to an acceptable alternative if 
available.  Common examples include aluminum and magnesium hydroxide 
containing antacids, coumadin, and phenytoin. 
• Diarrhea will be managed with the following regimen: loperamide (4 mg PO) at 
onset of symptoms, followed by 2 mg loperamide every 2 hours while awake (or 
4 mg PO every 4 hours while sleeping) up to a maximum of 16 mg loperamide 
per day.  Additional agents may be used concurrently if loperamide is not 
adequate to control diarrhea as a single agent. 
• The use of white cell growth factors is discouraged during the course of radiation 
but is allowed for management of neutropenia at physician discretion in 
concordance with ASCO guidelines. 
• Nausea and vomiting will be managed through the use of appropriate simple 
supportive measures (e.g., prochlorperazine). To date, 5 HT3 antagonists have not 
been routinely required but allowed if necessary. 
• Patients will receive full supportive care as needed while on this study including 
blood product support, intravenous hydration, antibiotic treatment and treatment 
of other newly diagnosed or concurrent medical conditions. 
• Patients should be advised to drink plenty of water or take rehydration fluids to 
avoid dehydration if diarrhea occurs. 
 
4.4  Duration of Therapy 
Treatment with AZD6244 will continue until the completion of chemoradiotherapy or until 
one of the following criteria applies: 
 
• 
Toxicity requiring discontinuation (section 4.2) 
• 
Disease progression, 
• 
Intercurrent illness that prevents further administration of treatment, 
• 
Unacceptable adverse event(s), 
• 
Patient decides to withdraw from the study, or 
• 
General or specific changes in the patient's condition render the patient 
unacceptable for further treatment in the judgment of the investigator. 
 
 
In the event of a discontinuation of AZD6244 for a dose limiting toxicity the patient will 
continue to receive capecitabine and radiotherapy if not already completed.   
 
4.5 Duration of Follow Up 
Patients will be followed for adverse events until three weeks after completion of 
chemoradiation. After this time they will be followed for the purpose of describing RTOG 
late toxicities until 36 months.  
 
4.6 Criteria for Removal from Study 
Patients will be removed from study after follow up has been completed as in section 4.5 or if  
 
• 
The patient refuses further follow up care at NIH 


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• 
General or specific changes in the patient's condition render the patient 
unacceptable for follow up in the judgment of the investigator 
• 
Death. 
 
The reason for study removal and the date the patient was removed must be documented in 
the Case Report Form. 
 
5.0 DOSING DELAYS/DOSE MODIFICATIONS 
5.1  AZD6244 
AZD6244 dose reductions will occur in the event of a DLT. In the event of a DLT that is an 
overlapping toxicity with Capecitabine, AZD6244 will be dose reduced.  If a Capecitabine 
associated toxicities occur following discontinuation of AZD6244, Capecitabine dose 
adjustments will occur as deemed appropriate by the Principal Investigator in conjunction 
with the participating Medical Oncology Associate Investigator.  AZD6244 dose reductions 
will not occur for established non-DLT Capecitabine toxicities (e.g. Grade 2 hand-foot 
syndrome).  
 
Dose de-escalation will occur as described in the table below for DLT’s and the following 
overlapping toxicities 
• Grade >3 diarrhea that persists despite appropriate medical management 
including anti-diarrheal medications 
• Grade >3 nausea and vomiting that persists despite appropriate medical 
management including anti-nausea medications 
• Grade 2 hand foot that persists despite interruption of capecitabine 
 
 
Dose De-Escalation Schedule 
Dose Level 
Dose 
 
AZD6244 
 
Capecitabine 
 
Radiation* 
 
 
Level -1 
 
50 mg PO QD 
Weeks 1-7 
 
825 mg/m2 PO 
every 12 hours 
Weeks 2-7 
 
5040 cGy 
Weeks 2-7 
 
 
Level 1 
 
50 mg PO BID 
Weeks 1-7 
 
825 mg/m2 PO 
every 12 hours 
Weeks 2-7 
 
5040 cGy 
Weeks 2-7 
 
 
Level 2 
 
75 mg PO BID 
Weeks 1-7 
 
825 mg/m2 PO 
every 12 hours 
Weeks 2-7 
 
5040 cGy 
Weeks 2-7 
* An additional 360 cGy may be delivered for fixed T4 tumors for a total dose of 
5400 cGy 
 
Diarrhea must be managed symptomatically. IV hydration and use of loperamide, as well as 
close observation, are recommended for diarrhea if clinically indicated.  C If control takes 


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longer than 2 days, medical evaluation including relevant diagnostic procedures, alternative 
treatment, and possible investigation of DPD deficiency should be considered. Capecitabine 
and AZD6244 may be held for up to 72 hours and will not be re-started until diarrhea has 
resolved to grade <1. In patients with grade 3 diarrhea evaluation for C. difficile colitis 
should be considered.  Patients with neutropenia and diarrhea should be considered for 
empiric use of prophylactic antibiotics such as oral quinolones.  
 
5.2 Capecitabine 
Capecitabine will be withheld in cases of Grade 3 or greater neutropenia or Grade 2 or 
greater hand-foot syndrome or mucositis that do not respond to medical management.  
Capecitabine will be restarted after the symptoms improved to Grade 1. The dose of 
Capecitabine may be adjusted in the event of recurrent Grade 2 or greater hand-foot 
syndrome, neutropenia, or other Capecitabine toxicities that have not been attributed to 
AZD6244. 
 
Summary of management of common Capecitabine toxicities during combined 
AZD6244 and Capecitabine dosing 
 
Toxicity 
Capecitabine dose modification 
Grade 2 hand foot syndrome 
Interrupt until ≤ grade 1. May then restart 
capecitabine at full dose. For second occurrence, 
hold capecitabine until ≤ grade 1, then restart 
capecitabine one dose level lower (75% of starting 
dose first occurrence, 50% of the starting dose the 
second occurrence, discontinue the third occurrence). 
Grade 3 hand foot syndrome 
Interrupt until ≤ grade 1. Then restart capecitabine 
one dose level lower (75% of starting dose first 
occurrence, 50% of the starting dose the second 
occurrence, discontinue the third occurrence). 
Grade 2 thrombocytopenia 
 
Continue at current dose 
Grade 3 thrombocytopenia 
Hold until recovery until < grade 1 then resume one 
dose level lower* 
Grade 4 thrombocytopenia 
Hold until recovery until < grade 1 then resume one 
dose level lower* 
Grade 3 neutropenia 
Hold until recovery until < grade 1 then resume one 
dose level lower* 
Grade 4 neutropenia 
Hold until recovery until < grade 1 then resume one 
dose level lower* 
> Grade 3 febrile neutropenia 
Hold until resolution of fever and neutropenia to < 
grade 1.  Then resume on dose level lower* 
*Dose reductions for capecitabine 
1.  Starting dose 
2.  75% of the starting dose 
3.  50% of the starting dose 


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4.  Discontinuation of capecitabine. 
 
 
5.3  Radiation 
Radiation dose will not be adjusted based on toxicity.  Delay in treatment may occur in the 
event that it is felt to be unsafe to deliver treatments due to the clinical status of the patient.  
Radiation treatment delays will be minimized as efficacy of radiotherapy is decreased with 
treatment delay.  In the event that radiation is delayed for a toxicity, treatment with 
AZD6244 and capecitabine will be held until resumption of radiation.  AZD6244 and 
capecitabine dose will be modified as described in section 5.1 and 5.2. 
 
6. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of AEs (Section 6.2) and the characteristics of an observed AE (Section 6.3) will 
determine whether the event requires expedited (via AdEERS) in addition to routine reporting.   
       
       6.1 Definitions 
           6.1.1 Adverse Event 
An adverse event is defined as any reaction, side effect, or untoward event that occurs 
during the course of the clinical trial associated with the use of a drug in humans, whether 
or not the event is considered related to the treatment or clinically significant. For this 
study, AEs will include events reported by the patient, as well as clinically significant 
abnormal findings on physical examination or laboratory evaluation. A new illness, 
symptom, sign or clinically significant laboratory abnormality or worsening of a pre-
existing condition or abnormality is considered an AE.  All AEs must be recorded on the 
AE case report form unless otherwise noted above in Section 6.1. 
All AEs, including clinically significant abnormal findings on laboratory evaluations, 
regardless of severity, will be followed until satisfactory resolution. AEs should be 
reported up to 30 days following the last dose of study drug.  AEs that are considered 
treatment related, expected, continuing, but not resolvable by 30 days after treatment 
completion (e.g., alopecia) will not be followed after the 30-day period.  
 
An abnormal laboratory value will be considered an AE if the laboratory abnormality is 
characterized by any of the following: 
• 
Results in discontinuation from the study 
• 
Is associated with clinical signs or symptoms  
• 
Requires treatment or any other therapeutic intervention 
• 
Is associated with death or another serious adverse event, including 
hospitalization.  
• 
Is judged by the Investigator to be of significant clinical impact 
• 
If any abnormal laboratory result is considered clinically significant, the 
investigator will provide details about the action taken with respect to the test 
drug and about the patient’s outcome. 


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6.1.2 Suspected adverse reaction 
Suspected adverse reaction means any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event. For the purposes of IND safety 
reporting, ‘reasonable possibility’ means there is evidence to suggest a causal relationship 
between the drug and the adverse event. A suspected adverse reaction implies a lesser 
degree of certainty about causality than adverse reaction, which means any adverse event 
caused by a drug. 
6.1.3 Unexpected adverse reaction 
An adverse event or suspected adverse reaction is considered “unexpected” if it is not 
listed in the investigator brochure or is not listed at the specificity or severity that has 
been observed; or, if an investigator brochure is not required or available, is not 
consistent with the risk information described in the general investigational plan or 
elsewhere in the current application. "Unexpected”, also refers to adverse events or 
suspected adverse reactions that are mentioned in the investigator brochure as occurring 
with a class of drugs or as anticipated from the pharmacological properties of the drug, 
but are not specifically mentioned as occurring with the particular drug under 
investigation. 
6.1.4 Serious  
An adverse event or suspected adverse reaction is considered serious if in the view of the 
investigator or the sponsor, it results in any of the following: 
• 
Death, 
• 
A life-threatening adverse drug experience 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
• 
A persistent or significant disability/incapacity 
• 
A congenital anomaly/birth defect. 
• 
Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered a serious adverse drug experience 
when, based upon appropriate medical judgment, they may jeopardize the patient 
or subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. 
6.1.5 Disability 
 A substantial disruption of a person’s ability to conduct normal life functions. 
6.1.6 Life-threatening adverse drug experience 
Any adverse event or suspected adverse reaction that places the patient or subject, in the 
view of the investigator or sponsor, at immediate risk of death from the reaction as it 
occurred, i.e., it does not include a reaction that had it occurred in a more severe form, 
might have caused death. 


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6.1.7 Protocol Deviation (NIH Definition) 
A protocol deviation is any change, divergence, or departure from the study design or 
procedures of a research protocol that is under the investigator’s control and that has not 
been approved by the IRB.  
6.1.8 Protocol Violation (NIH Definition) 
Any change, divergence, or departure from the study procedures in an IRB-approved 
research protocol that has a major impact on the subject’s rights, safety, or well-being 
and/or the completeness, accuracy or reliability of the study data. 
 
6.1.9 Unanticipated Problem 
Any incident, experience, or outcome that: 
•  Is unexpected in terms of nature, severity, or frequency in relation to  
(a) the research risks that are described in the IRB-approved research protocol and 
informed consent document; Investigator’s Brochure or other study documents, 
and 
(b) the characteristics of the subject population being studied; AND 
• Is related or possibly related to participation in the research; AND 
• Places subjects or others at a greater risk of harm (including physical, 
psychological, economic, or social harm) than was previously known or 
recognized. 
 
6.2 Comprehensive Adverse Events and Potential Risks Lists (CAEPRs) 
6.2.1 CAEPRs for CTEP-Supplied Investigational Agent(s) 
 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a single, 
complete list of reported and/or potential adverse events (AE) associated with an agent 
using a uniform presentation of events by body system.  In addition to the comprehensive 
list, a subset, the Agent Specific Adverse Event List (ASAEL), appears in a separate 
column and is identified with bold and italicized text.  This subset of AEs (the ASAEL) 
contains events that are considered ‘expected’ for expedited reporting purposes only.  
Refer to the “CTEP, NCI Guidelines: Adverse Event Reporting Requirements” 
(http://ctep.cancer.gov/reporting/adeers.html) for further clarification.  The CAEPR may 
not provide frequency data; if not, refer to the Investigator’s Brochure for this 
information. 
 
6.2.1.1 
CAEPR for AZD6244 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
 
Selumetinib (AZD6244 Free base [NSC 741078], AZD6244 Hydrogen sulfate [NSC 748727]) 
 


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The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a single list of reported 
and/or potential adverse events (AE) associated with an agent using a uniform presentation of events by 
body system. In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to 
Expedited Reporting (SPEER), appears in a separate column and is identified with bold and italicized 
text. This subset of AEs (SPEER) is a list of events that are protocol specific exceptions to expedited 
reporting to NCI via AdEERS (except as noted below).  Refer to the 'CTEP, NCI Guidelines: Adverse 
Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for further 
clarification. Frequency is provided based on 665 patients. Below is the CAEPR for Selumetinib 
(AZD6244). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to the 
AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple investigational 
agents and has an AE listed on different SPEERs, use the lower of the grades to determine if 
expedited reporting is required. 
Version 2.3, September 27, 20111 
 
 Adverse Events with Possible  
 Relationship to Selumetinib (AZD6244)  
 (CTCAE 4.0 Term) 
[n= 665] 
 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
 
 (formerly known as ASAEL) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
Anemia 
 
 Anemia (Gr 3) 
 
 
Febrile neutropenia2 
  
CARDIAC DISORDERS 
  
 
 
Left ventricular systolic 
dysfunction 
 Left ventricular systolic 
dysfunction (Gr 2) 
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 2) 
 
Constipation 
 
 Constipation (Gr 2) 
Diarrhea3 
 
 
 Diarrhea3 (Gr 3) 
 
Dry mouth 
 
  
 
Mucositis oral 
 
 Mucositis oral (Gr 2) 
Nausea 
 
 
 Nausea (Gr 3) 
Vomiting 
 
 
 Vomiting (Gr 2) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Edema face 
 
 Edema face (Gr 2) 
Edema limbs 
 
 
 Edema limbs (Gr 2) 
Fatigue 
 
 
 Fatigue (Gr 2) 
 
Fever 
 
 Fever (Gr 2) 
INVESTIGATIONS 
  
 
Alanine aminotransferase 
increased 
 
 Alanine aminotransferase 
increased (Gr 3) 
 
Alkaline phosphatase increased  
  
 
Aspartate aminotransferase 
increased 
 
 Aspartate aminotransferase 
increased (Gr 3) 
 
Platelet count decreased 
 
  
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
 Anorexia (Gr 2) 
 
Hypoalbuminemia 
 
  
 
Hypomagnesemia 
 
  


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NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
  
 
Headache 
 
 Headache (Gr 2) 
PSYCHIATRIC DISORDERS 
  
 
Insomnia 
 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
 Cough (Gr 2) 
 
Dyspnea 
 
 Dyspnea (Gr 2) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Dry skin 
 
 Dry skin (Gr 2) 
 
Pruritus 
 
  
Rash acneiform 
 
 
 Rash acneiform (Gr 3) 
Rash maculo-papular 
 
 
 Rash maculo-papular (Gr 2) 
VASCULAR DISORDERS 
  
 
Hypertension 
 
  
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 
Principal Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV .  Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail. 
 
2Febrile neutropenia/neutropenic infection has been observed primarily in trials combining Selumetinib 
(AZD6244) and docetaxel. 
 
3SBE-CD (Captisol®, vehicle) in the mix and drink formulation is known to cause soft stools and/or 
diarrhea in rats and dogs; however, it is possible that some of these findings might be related to 
exacerbation of the vehicle effect by Selumetinib (AZD6244). 
 
4Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
 
Also reported on Selumetinib (AZD6244) trials but with the relationship to Selumetinib (AZD6244) 
still undetermined: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other 
(hemorrhagic anemia) 
CARDIAC DISORDERS - Acute coronary syndrome; Cardiac disorders - Other (Takatsubo 
cardiomyopathy syndrome); Chest pain - cardiac; Heart failure; Palpitations; Right ventricular dysfunction; 
Sinus bradycardia 
EYE DISORDERS - Blurred vision; Extraocular muscle paresis; Eye disorders - Other (bilateral macular 
edema); Eye disorders - Other (black haze in line of vision); Eye disorders - Other (elevated intraocular 
pressure); Flashing lights; Glaucoma; Retinopathy 
GASTROINTESTINAL DISORDERS - Abdominal distension; Ascites; Colitis; Dyspepsia; Esophagitis; 
Flatulence; Gastric hemorrhage; Gastroesophageal reflux disease; Ileal stenosis 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Flu like symptoms; Non-cardiac 
chest pain 
HEPATOBILIARY DISORDERS - Hepatic failure; Hepatobiliary disorders - Other (cholangitis) 
INFECTIONS AND INFESTATIONS - Infection4 
INVESTIGATIONS - CPK increased; Creatinine increased; Electrocardiogram QT corrected interval 
prolonged; Neutrophil count decreased; Weight gain 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hypokalemia; Hyponatremia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; Back pain; Generalized 
muscle weakness; Musculoskeletal and connective tissue disorder -  Other (joint swelling); 
Musculoskeletal and connective tissue disorder -  Other (rhabdomyolysis); Myalgia; Myositis; Pain in 
extremity 


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NERVOUS SYSTEM DISORDERS - Cognitive disturbance; Depressed level of consciousness; 
Dysgeusia; Dysphasia; Ischemia cerebrovascular; Leukoencephalopathy; Memory impairment; Nervous 
system disorders - Other (numbness); Nervous system disorders - Other (spinal cord compression); 
Oculomotor nerve disorder; Peripheral sensory neuropathy; Reversible posterior leukoencephalopathy 
syndrome; Seizure 
PSYCHIATRIC DISORDERS - Confusion; Depression 
RENAL AND URINARY DISORDERS - Acute kidney injury; Proteinuria 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory distress syndrome; 
Epistaxis; Hypoxia; Pharyngolaryngeal pain; Pleural effusion; Pneumonitis; Sore throat; Voice alteration 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Pain of skin; Palmar-plantar 
erythrodysesthesia syndrome; Photosensitivity; Scalp pain; Skin and subcutaneous tissue disorders - 
Other (angular cheilitis, unilateral); Skin and subcutaneous tissue disorders - Other (skin fissures) 
VASCULAR DISORDERS - Hypotension; Thromboembolic event 
 
 
Note:  Selumetinib (AZD6244) in combination with other agents could cause an exacerbation of any 
adverse event currently known to be caused by the other agent, or the combination may result in events 
never previously associated with either agent. 
 
  
 
 
6.2.1.2 
Adverse Event List for Capecitabine 
Capecitabine may cause diarrhea, sometimes severe.  Standard anti-diarrheal treatments 
are recommended and dose reductions are employed for reoccurrence of grade 3 diarrhea.  
Grade 3 or 4 toxicities are described below for patients receiving Capecitabine as a single 
agent:  diarrhea (12%), nausea (2%), stomatitis (2%), vomiting (2%), abdominal pain 
(3%), hand- and –foot syndrome (17%), decreased neutrophils/granulocytes (2.4%), 
hyperbilirubinemia (20%), decreased lymphocytes (13%).  A comprehensive list of 
adverse events observed with Capecitabine can be found in the package insert.  Diarrhea 
and rash are overlapping toxicities of AZD6244 and capecitabine and will be 
aggressively managed as per section 5.1. 
 
6.3 Adverse Event Characteristics  
• 
CTCAE term (AE description) and grade:  The descriptions and grading scales 
found in the revised NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 will be utilized for AE reporting.  All appropriate treatment 
areas should have access to a copy of the CTCAE version 4.0.  A copy of the CTCAE 
version 4.0 can be downloaded from the CTEP web site (http://ctep.cancer.gov). 
 
• 
‘Expectedness’: AEs can be ‘Unexpected’ or ‘Expected’ (see Section 6.1 above) for 
expedited reporting purposes only.  ‘Expected’ AEs (the ASAEL) are bold and 
italicized in the CAEPR (Section 6.2.1.1). 
 
• 
Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 


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• 
In addition, the study will use the RTOG/EORTC Radiation Morbidity Scoring 
Scheme to score side effects of radiation treatment for descriptive purposes.  These 
criteria are available from the RTOG website 
http://rtog.org/members/toxicity/main.html 
 
6.4 Expedited Adverse Event Reporting 
6.4.1 Expedited AE reporting for this study must use AdEERS (Adverse Event 
Expedited Reporting System), accessed via the CTEP home page (http://ctep.cancer.gov).  
The reporting procedures to be followed are presented in the “CTEP, NCI Guidelines: 
Adverse Event Reporting Requirements” which can be downloaded from the CTEP home 
page (http://ctep.cancer.gov).  These requirements are briefly outlined in the table below 
(Section 6.4.2). 
 
In the rare event when Internet connectivity is disrupted a 24 hour-hour notification is to 
be made to NCI by telephone at: 301-897-7497 for CIP studies.  An electronic report 
MUST be submitted immediately upon re-establishment of internent connection. Please 
note that all paper AdEERS forms have been removed from the CTEP website and will 
NO LONGER be accepted.  
 
6.4.2 Expedited Reporting Guidelines – AdEERS Reporting Requirements for Adverse 
Events That Occur Within 30 Days1 of the Last Dose of the Investigational Agent on 
Phase 1 Trials 
 
 
 
Phase 1 Trials 
 
 
Grade 1 
 
Grade 2 
 
Grade 2 
 
Grade 3 
 
Grade 3 
Grades 
4 & 52 
Unexpected 
and 
Expected 
 
Unex-
pected 
 
 
Expected 
Unexpected 
Expected 
Unexpected  
and 
Expected 
with  
Hospitali-
zation 
without 
Hospitali- 
zation 
with  
Hospitali- 
zation 
without 
Hospitali- 
zation 
Unrelated 
Unlikely 
Not 
Required 
Not 
Required 
Not 
Required 
10 
Calendar 
Days 
Not 
Required 
10 
Calendar 
Days 
Not 
Required 
24-Hour; 
5 Calendar 
Days 
Possible 
Probable 
Definite 
Not 
Required 
10 
Calendar 
Days 
Not 
Required 
24-Hour; 
5 Calendar 
Days 
24-Hour; 
5 Calendar 
Days 
10 
Calendar 
Days 
Not 
Required 
24-Hour; 
5 Calendar 
Days 
1 Adverse events with attribution of possible, probable, or definite that occur greater than 30 days after 
the last dose of treatment with an agent under a CTEP IND require reporting as follows: 
AdEERS 24-hour notification followed by complete report within 5 calendar days for: 
• 
Grade 3 unexpected events with hospitalization or prolongation of hospitalization 
• 
Grade 4 unexpected events  
• 
Grade 5 expected events and unexpected events 
 
2 Although an AdEERS 24-hour notification is not required for death clearly related to progressive disease, a full 
report is required as outlined in the table. 
December 15, 2004 
 
Note:  All deaths on study require both routine and expedited reporting 


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regardless of causality.  Attribution to treatment or other cause must be 
provided. 
 
• Expedited AE reporting timelines defined: 
 “24 hours; 5 calendar days” – The investigator must initially report the AE 
via AdEERS within 24 hours of learning of the event followed by a 
complete AdEERS report within 5 calendar days of the initial 24-hour 
report. 
 “10 calendar days” - A complete AdEERS report on the AE must be 
submitted within 10 calendar days of the investigator learning of the 
event.  
 
• Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates 
hospitalization (or prolongation of existing hospitalization) must be reported 
regardless of attribution and designation as expected or unexpected with the 
exception of any events identified as protocol-specific expedited adverse event 
reporting exclusions.   
 
• Any event that results in persistent or significant disabilities/incapacities, 
congenital anomalies, or birth defects must be reported via AdEERS if the event 
occurs following treatment with an agent under a CTEP IND. 
 
• 
Use the NCI protocol number and the protocol-specific patient ID assigned during 
trial registration on all reports. 
 
6.4.3 Protocol-Specific Expedited Adverse Event Reporting Exclusions 
 Toxicities of surgery will not be collected as adverse events.  Adverse events will be 
recorded and reported until three weeks after the completion of chemoradiotherapy for all 
patients.  From 3 weeks following chemoradiation until 3 years of follow-up only the 
RTOG late toxicity scoring schema will be collected. 
 
6.4.4 NCI-IRB Reporting  
       6.4.4.1 NCI-IRB Expedited Reporting of Adverse Events, Unanticipated Problems, 
and Deaths 
 
The NCI-IRB requires that the following language be used for reporting Expedited 
Adverse Events to the NCI-IRB: 
 
The Protocol PI will report to the NCI-IRB: 
• All unexpected serious adverse events that are possibly, probably, or definitely 
related to the research  
• All deaths, except deaths due to progressive disease  
• All Protocol Violations or Deviations 
• All Unanticipated Problems 
Reports must be received by the NCI-IRB within 7 working days of PI awareness via 


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iRIS. 
 
       6.4.4.2 NCI-IRB Requirements for PI Reporting of Adverse Events at Continuing 
Review 
For reporting of adverse events at time of continuing review, the NCI-IRB requires a 
summary report of adverse events that have occurred on the protocol since the previous 
continuing review and in aggregate. The method of presentation should provide the 
NCI-IRB with the information necessary to clearly identify risks to participants and to 
make a risk: benefit determination. The summary report is based on the following 
guidance: any unexpected severity and/or unexpected frequency of expected events needs 
to be reported and interpreted in relation to the risk: benefit of study participants in the 
narrative. 
The following table is recommended for use of reporting: 
CTCAE 
Term 
Grade 
# of Events 
since last 
CR 
Total # 
of 
Events 
Attribution 
to IND 
Attribution 
to Research 
Listed in 
Consent? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The protocol PI will report to the NCI-IRB:  
1. 
All Grade 2 unexpected events that are possibly, probably or definitely related to 
the research;  
2. 
All Grade 3 and 4 events that are possibly, probably or definitely related to the 
research;  
3. 
All Grade 5 events regardless of attribution;  
4. 
All Serious Events regardless of attribution.  
NOTE: Grade 1 events are not required to be reported.  
       6.4.4.3 NCI-IRB Reporting of IND Safety Reports 
Only IND Safety Reports that require a sponsor recommended change to the protocol or 
the consent form or in the opinion of the PI increases risks to study participants will need 
to be reported to the NCI IRB. 
This is based on the January 15, 2007 OHRP Guidance “Guidance for Reviewing and 
Reporting Unanticipated Problems Involving Risks to Subjects or Others and Adverse 
Events” under Section B. Reporting of external adverse events by investigators to IRBs: 
http://www.hhs.gov/ohrp/policy/AdvEvntGuid.htm 


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      6.5 IND Sponsor Reporting; Refer to 6.2 and 6.4 
An investigator must immediately report to the sponsor any serious adverse event, 
whether or not considered drug related, including those listed in the protocol or 
investigator brochure and must include an assessment of whether there is a reasonable 
possibility that the drug caused the event.  
 
Study endpoints that are serious adverse events (e.g. all-cause mortality) must be reported 
in accordance with the protocol unless there is evidence suggesting a causal relationship 
between the drug and the event (e.g. death from anaphylaxis).  In that case, the 
investigator must immediately report the death to the sponsor. 
 
6.6 FDA Reporting Criteria 
     6.6.1 IND Safety Reports to the FDA (Refer to 21 CFR 312.32) 
 
 
 
6.6.1.1 Expedited Reporting to the FDA 
The Sponsor will notify FDA  via phone, fax, or email of any unexpected fatal or 
life-threatening suspected adverse reactions as soon as possible but no later than 7 
calendar days of initial receipt of the information. This will be followed with a 
written report within 15 days using the MedWatch Form 3500a.  
The study Sponsor will notify FDA in writing of any suspected adverse reaction 
that is both serious and unexpected as soon as possible but no later than 15 
calendar days after initial receipt of the information using the MedWatch Form 
3500a. If FDA requests any additional data or information, the sponsor must 
submit it to the FDA as soon as possible, but no later than 15 calendars days after 
receiving the request.  
The study Sponsor will also report expeditiously as above: 
• any findings from clinical, epidemiological, or pooled analysis of multiple 
studies or any findings from animal or in vitro testing that suggest a 
significant risk in humans exposed to the drug 
• clinically important increase in the rate of a serious suspected adverse 
reaction over that listed in the protocol or investigator brochure.  
 
6.6.1.2 Exclusions to expedited reporting to the FDA 
The following events will not be reported in an expedited manner but will be 
included in the annual report:  
        
6.6.1.3 FDA Annual Reports (Refer to 21 CFR 312.33) 
The study Sponsor will submit a brief report annually of the progress of the trial 
within 60 days of the anniversary date that the IND went into effect as indicated 
in 21CFR 312.33, and any associated FDA correspondences regarding the IND 
annual report.  
 
 


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6.7 Secondary AML/MDS 
All secondary malignancies that occur following treatment will be reported through 
AdEERS, CTCAE v4.0. 
 
6.8 Data and Safety Monitoring Plan 
 
      6.8.1 Principal Investigator/Research Team 
The clinical research team will meet on a regular basis weekly when patients are 
being actively treated on the trial to discuss each patient. Decisions about dose level 
enrollment and dose escalation if applicable will be made based on the toxicity data 
from prior patients.  
 
All data will be collected in a timely manner and reviewed by the principal 
investigator or a lead associate investigator. Adverse events will be reported as 
required above. Any safety concerns, new information that might affect either the 
ethical and or scientific conduct of the trial, or protocol deviations and violations will 
be immediately reported to the IRB using iRIS and if applicable to the Sponsor.  
 
The principal investigator will review adverse event and response data on each patient 
to ensure safety and data accuracy. The principal investigator will personally conduct 
or supervise the investigation and provide appropriate delegation of responsibilities to 
other members of the research staff.  
 
 
     6.8.2 Sponsor Monitoring Plan 
 
 
 
     Data reporting as per 12.1. 
 
7.  Human Subjects Protection 
7.1   Rationale for Subject Selection 
This study will be open to all individuals regardless of gender, ethnicity, or race provided 
that the aforementioned inclusion and exclusion criteria are met. For safety reasons, pregnant 
women and children are excluded from this study. This study will be recruited through 
internal referral, our physician referral base, and through various cancer information hotlines 
(i.e., Clinical Studies Support Center, 1-800-4Cancer.) Participants should realize that there 
is no guarantee of benefit to them from participation in this trial. The results of this trial may 
benefit future cancer patients. To date, there is no information that suggests that differences 
in drug metabolism or effect on tumor would be expected in one ethnic group compared to 
another. Efforts will be made to extend accrual to each representative population, but a 
balance must be struck between participant safety considerations and limitations on the 
number of individuals exposed to potentially ineffective treatments on the one hand and the 
need to explore racial/ethnic aspects of clinical research on the other hand.  If differences in 
outcome that correlate to ethnic identity are noted, a follow-up study may be written to 
investigate those differences more fully. Inclusion of Women and Minorities:  This study will 
be open to all individuals regardless of gender, ethnicity, or race provided that the 
aforementioned inclusion and exclusion criteria are met. 
 
7.2 Justification for Exclusions 


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Pregnant women are excluded from this study because the effects of AZD6244 on the 
developing fetus is unknown and because radiation is a known teratogen.  Because there is an 
unknown but potential risk for adverse events in nursing infants secondary to treatment of the 
mother with AZD6244, breastfeeding should be discontinued if the mother is treated with 
AZD6244. Participants with unstable or serious medical conditions such as uncontrolled 
diabetes, uncontrolled hypertension, symptomatic congestive heart failure, unstable angina 
pectoris, myocardial infarction within the past 6 months, uncontrolled cardiac arrhythmia; or 
psychiatric illness/social situations that would limit compliance with study requirements are 
excluded due to the possibility that the underlying condition may obscure the attribution of 
effect and adverse events and may limit study compliance. HIV-positive patients on 
combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic 
interactions with AZD6244.  Appropriate studies will be undertaken in patients receiving 
combination antiretroviral therapy when indicated. 
 
7.3 Participation of Children 
This study includes patients 18 years of age and older. Because insufficient 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 may be eligible for future pediatric trials. Studies 
will be performed in patients <18 years of age when it is appropriate to do so. 
 
7.4 Evaluation of Benefits and Risks/Discomforts 
There may or may not be any clinical benefit to a patient from participation in this trial. Their 
participation will benefit future cancer patients. Potential risks include the possible 
occurrence of any of a range of side effects that are listed in the consent document. It is 
possible that the side effects of radiation treatment and Capecitabine may be increased with 
AZD6244.  The procedure for protecting against or minimizing risks will be to exclude 
patients with known contraindications to this therapy and to medically evaluate patients as 
described in protocol Section 3.3. Although no compensation is available, any injury will be 
fully evaluated and treated in keeping with the benefits or care to which participants are 
entitled under applicable regulations. 
 
Optional biopsies will be obtained during sigmoidoscopy.  The risks of sigmoidoscopy 
include discomfort during the procedure, bleeding, infection, gas, and the remote risk of 
perforation. 
 
7.5 Consent and Assent Process and Documentation 
An associate or principal investigator on the trial will inform patients of the purpose, 
alternatives, drug administration plan, research objectives and follow-up of this trial. The 
patient will be provided an IRB-approved consent for review and signature and his/her 
questions will be answered. After a decision is made to enroll into the study, a signature will 
be obtained from the patient. The original signed consent goes to Medical Records; a copy 
will be placed in the research record.  All patients must have a signed informed consent form 
and an on-study (confirmation of eligibility) form filled out and signed by a participating 
investigator before entering on study. 
 
7.6 Procedure for Protecting Against or Minimizing Any Potential Risks 


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All care will be taken to minimize side effects, but they can be unpredictable in nature and 
severity. This study may involve risks to patients, which are currently unforeseeable. All 
patients will be monitored for side effects from taking study medication. This research 
represents a greater than minimal risk to participants, but presents the prospect of direct 
benefit to individual subjects. 
 
7.6.1 Patient Advocate 
The patients’ rights representative is available to patients receiving treatment on this 
protocol at the NIH Clinical Center at (301) 496-2626 in Building 10 of the Clinical 
Research Center, Room 1-3521, on the Bethesda NIH campus. Patients will be informed 
that they can contact the study PI or RN at any time with questions about their medical 
care, and that the patients’ rights representative is also available to answer nonmedical 
questions about the study. 
 
8. PHARMACEUTICAL INFORMATION 
A list of the adverse events and potential risks associated with the investigational or commercial 
agents administered in this study can be found in Section 6.1. 
8.1  
CTEP-Supplied Investigational Agent(s)  
8.1.1  AZD6244 Hydrogen Sulfate (NSC 748727) 
• 
Chemical Name:  6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-
carboxylic acid (2-hydroxy-ethoxy)-amide hydrogen sulfate 
• 
Other Names:  ARRY-142886;  AR00142866;  AR-142886-01 
• 
Classification:  Mitogen-activated protein kinase (MEK) inhibitor 
• 
CAS Registry Number:   943332-08-9 
• 
Molecular Formula:   C17H15BrClFN4O3 ·  H2SO4 
• 
M.W.:  555.7 
• 
Solubility:   Solubility in Captisol® approximately 1 mg/mL at 25°C.   Very low 
aqueous solubility (3.4 mcg/mL at pH 7.4).  
• 
Mode of Action:  The RAS/RAF/MEK/ERK pathway is an important mediator of many 
cellular processes including proliferation, survival, differentiation, apoptosis, motility, 
and metabolism.  This pathway is often aberrantly activated in human tumors due to the 
overexpression of activated K-RAS, mutant b-Raf, or other growth factor receptors. 
AZD6244 is a selective mitogen-activated protein kinase (MEK) inhibitor.  By 
inhibiting MEK, AZD6244 inhibits ERK phosphorylation.  Thus, AZD6244 may inhibit 
oncogenic growth signaling in tumor cells by targeting the RAS/RAF/MEK/ERK 
pathway. 
• 
How Supplied:    AZD6244 hydrogen sulfate is supplied as a 25 mg, size 4, plain, 
white,  hydroxypropylmethylcellulose (HPMC) capsule in white high density 
polyethylene (HDPE) containers  with foil-lined, induction-sealed, child-resistant 
closures.  Each bottle contains 60 capsules.   Each capsule contains a dispersion of 
AZD6244 hydrogen sulfate in d-α-tocopheryl polyethylene glycol 1000 succinate 
(TPGS; a water soluble form of vitamin E).   
• 
Storage:  Store the AZD6244 hydrogen sulfate capsules at room temperature (20°C-
25°C). Brief excursions are permitted between 15°C and 30°C.    
• 
Stability:  Stability studies are ongoing.   
• 
Route of Administration:   Oral.  Take AZD6244 capsules on an empty stomach 


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(either 1 hour before or 2 hours after meals).  AZD6244 capsules should be taken with 
water only.    
• 
Potential Drug Interactions:  AZD6244 is primarily metabolized by CYP1A2 to N-
desmethyl AZD6244 which is 3-5 fold more pharmacologically active than AZD6244.   
 
 
In vitro, AZD6244 is metabolized to a lesser extent by CYP2C19 and CYP3A4.  
In vitro, AZD6244 is a weak inhibitor of CYP2C9 and CYP1A2.    
 
High vitamin E doses may potentiate warfarin’s anticoagulant activity.  Monitor PT/INR 
more frequently in patients receiving both warfarin and AZD6244 hydrogen sulfate 
capsules.  Avoid concomitant intake of Vitamin E in excess of 100% of the recommended 
daily dose.  
 
8.1.2 Agent Ordering 
AZD6244 (NSC 748727) may be requested by the Principal Investigator (or their 
authorized designee) at each participating institution.  Pharmaceutical Management 
Branch (PMB) policy requires that agent be shipped directly to the institution where the 
patient is to be treated.  PMB does not permit the transfer of agents between institutions 
(unless prior approval from PMB is obtained.)  The CTEP-assigned protocol number 
must be used for ordering all CTEP-supplied investigational agents.  The responsible 
investigator at each participating institution must be registered with CTEP, DCTD 
through an annual submission of FDA form 1572 (Statement of Investigator), Curriculum 
Vitae, Supplemental Investigator Data Form (IDF), and Financial Disclosure Form 
(FDF).  If there are several participating investigators at one institution, CTEP-supplied 
investigational agents for the study should be ordered under the name of one lead 
investigator at that institution. 
 
Agent may be requested by completing a Clinical Drug Request (NIH986) and faxing it 
to the Pharmaceutical Management Branch at (301) 480-4612.  For questions about drug 
orders, transfers, returns, or accountability call (301) 496-5725 Monday through Friday 
between *:30 am and 4:30 pm (ET) or email PMBAfterHours@mail.nih.gov anytime. 
 
8.1.3 Agent Accountability 
Agent Inventory Records – The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the inventory and disposition of all agents 
received from DCTD using the NCI Drug Accountability Record Form (DARF).  (See 
the CTEP home page at http://ctep.cancer.gov for the Procedures for Drug Accountability 
and Storage and to obtain a copy of the DARF and Clinical Drug Request form.) 
 
 
8.2     Commercial Agent(s): 
8.2.1  Capecitabine 
Chemical Name:  5’-deoxy-5-fluoro-N-[(pentyloxy) carbonyl]-cytidine 
Other Names:  xeloda 
Classification:  Fluoropyrimidine carbamate 
M.W.:  359.35 


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Solubility:   Aqueous solubility of 26 mg/mL at 20ºC.  
Mode of Action:  Capecitabine is readily absorbed in the gastrointestinal tract and 
hydrolyzed in the liver to 5’-deoxy-5-fluorocytadine (5’-DFCR).  Cytidine deaminase 
converts 5’-DFCR to 5’-deoxy-5-fluorodine (5’-DFUR) which is further hydrolyzed to the 
active drug 5-FU.  5-FU is metabolized to 5-fluoro-2’deoxyuridine monophosphate 
(FdUMP) and 5-fluorouridine triphosphate (FUTP).  FdUMP binds covalently to 
thymidylate synthase and thereby inhibits the formation of thymidylate from 2’-
deoxyuridylate.  Thymidylate is the necessary precursor of thymidine triphosphate, which is 
essential for the synthesis of DNA, so that a deficiency of this compound can inhibit cell 
division.  Nuclear enzymes can mistakenly incorporate FUTP in place of uridine 
triphosphate during synthesis of RNA which can interfere with RNA processing and protein 
synthesis. 
How Supplied:    Capecitabine is supplied as a biconvex oblong film coated caplet 
containing either 150 mg of capecitabine or 500 mg of capecitabine.  The inactive 
ingredients in capecitabine include anhydrous lactose, croscarmellose sodium, 
hydroxypropyl methycellulose, microcrystalline cellulose, magnesium stearate, and 
purified water.  The film coating contains hydroxypropyl cellulose, talc, titanium dioxide, 
and synthetic yellow and red iron oxides. 
Storage:   Store at 25° C; excursions permitted to 15 to 30° C.  
Route of Administration:   Oral.        
Potential Drug Interactions:  Administration with Warfarin can increase the INR beyond 
expected.  Capecitabine should not be administered with aluminum hydroxide or 
magnesium hydroxide containing antacids, such as Maalox, as it may increase the plasma 
concentrations of capecitabine and its metabolites.  
Source:  Capecitabine will be purchased from commercial sources by the NIH Clinical 
Center Pharmacy Department. 
Note:  The reader is referred to the capecitabine package insert for additional 
information. 
 
9. CORRELATIVE/SPECIAL STUDIES 
9.1 
Laboratory Correlative Studies 
9.1.1 Tumor Biopsies 
 
9.1.1.1Tumor mutational status – Laboratory Correlative Study #1 
• Collection of specimens:  Biopsy specimen will be obtained at the time of 
pretreatment endoscopy.  If sufficient tissue is available for this study from 
the initial diagnostic biopsy, this biopsy will not be performed. 
• Handling of Specimens:  biopsies will be collected, immediately placed in 
sterile saline on wet ice, and transported to the laboratory of Deborah Citrin.  
Specimens will centrifuged to remove supernatant and frozen at -80 C until 
use. 
 
9.1.1.2 Tumor ERK1/2 phosphorylation – Laboratory Correlative Study #2) 
• Collection of Specimen:  Specimen will be collected at the time of 
pretreatment endoscopy and on day 8 and day 15.  If sufficient tissue is 
available for this study from the initial diagnostic biopsy, the pretreatment 
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• Handling of Specimens:  The specimen will be submitted to pathology in 
formalin for processing and immunohistochemistry. 
 
9.1.2 Research Labs 
 
9.1.2.1 Peripheral mononuclear cell ERK1/2 phosphorylation – Laboratory 
Correlative Study #3) 
• Collection of Specimen:  A whole blood specimen will be collected 
pretreatment, day 8, day 15, and at four weeks of follow up (week 11).  
Nurses at the Radiation Oncology clinic will collect whole blood in one 10 cc 
EDTA tube. 
• Handling of Specimens:  Whole blood will be collected and transported 
immediately to the laboratory of Deborah Citrin for processing for flow 
cytometric analysis. 
 
 
9.1.2.2 Plasma TGFα – Laboratory Correlative Study #4) 
• Collection of Specimen:  Specimen will be collected pretreatment, day 8, day 
15, and at four weeks of follow up (week 11). Nurses at the Radiation 
Oncology clinic will collect whole blood in one 10 cc EDTA tube for plasma. 
• Handling of Specimens:  Blood for plasma will be immediately transported on 
ice to the laboratory of Deborah Citrin.  Plasma will be processed within 15 
minutes of collection.  Aliquots will be stored at -80 C until use. 
 
9.2  Sample processing 
Biospecimens will be collected and processed using validated SOPs that will ensure both 
specimen quality and patient confidentiality pursuant to informed consent provisions. 
 
Using a computerized inventory system and a backup hardcopy process, all specimen 
collection and processing steps will be documented and the specific location of each 
specimen will be tracked. Each new specimen collected will be assigned a unique barcode 
identifier that can be linked to the original specimen collected and other relevant information 
within the inventory system. To ensure patient confidentiality, only containers used for the 
initial specimen collections will be labeled with patient identifiers. Only the barcode 
identifier will be applied to all subsequent specimen containers. When specimens are 
processed and aliquoted, no patient information will be included on the new containers. 
Original specimen containers will be discarded. Only barcode-labeled specimens without 
patient identifiers will be sent for analysis and/or storage. Specimen labels will indicate: 
protocol number, order in which the patient enrolled on the trial, type of sample, collection 
time, and total volume collected, as appropriate. Samples from sets of at least three patients 
will be grouped for scientific analysis. 
 
The inventory process contains other security provisions sufficient to safeguard patient 
privacy and confidentiality. Access to the inventory system and associated documents will 
be restricted to appropriate individuals. Requests to use specimens stored in the repository 
must be approved. The only patient information available in the inventory system will be the 
patient sex, diagnosis, and level of informed consent given. SOPs ensure that any changes in 
informed consent made by a patient and relayed to the PI will be reflected in the inventory 


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system to ensure that specimens are destroyed as appropriate. All laboratory personnel will 
be trained to adhere to SOPs and will be monitored for high-quality performance. 
 
Following completion of this study, samples will remain in storage as detailed above. Access 
to these samples will only be granted following IRB approval of an additional protocol, 
granting the rights to use the material.  
 
If, at any time, a patient withdraws from the study and does not wish for their existing 
samples to be utilized, the individual must provide a written request. Following receipt of this 
request, the samples will be destroyed (or returned to the patient, if so requested), and 
reported as such to the IRB. Any samples lost (in transit or by a researcher) or destroyed due 
to unknown sample integrity (i.e., broken freezer allows for extensive sample thawing, etc.) 
will be reported as such to the IRB. 
 
Any new use of these samples will require prospective IRB review and approval; any loss or 
destruction of samples and the planned disposition of samples after the protocol is terminated 
will be reported to the IRB. 
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 
below. 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 participants 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 office of the CCR, NCI. 
 
 
10. 
STUDY CALENDAR 
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. 
  
 
Pre- 
Study 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
Wk 
9 
Wkh 
11 
Follow up 
3, 6, 9, 12, 24, 
and 36 months 
after 
completion of 
chemoradiation 
AZD6244 
 
A 
A 
A 
A 
A 
A 
A 
 
 
 
 


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Capecitabine 
 
 
B 
B 
B 
B 
B 
B 
 
 
 
 
Radiation 
 
 
C 
C 
C 
C 
C 
C 
 
 
 
 
Informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Ophthalmologic 
examinatione 
Xf 
 
 
 
 
 
 
 
 
 
 
 
Surgical Consult 
 Xf 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
Concurrent 
meds 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
Physical exam 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
Vital signs with 
pulse oximetry 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
 
 
 
 
 
 
 
 
X 
X 
Performance 
status 
X 
 
 
 
 
 
 
 
 
 
 
 
CBC w/diff, 
plts, PT/PTT 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum 
chemistrya 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
EKG  
X 
Xi 
Xi 
 
Xi 
 
 
 
 
 
 
 
Adverse event 
evaluation 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xg 
Tumor 
measurements 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
Radiologic 
evaluation 
 
X 
 
 
 
 
 
 
 
 
 
X 
X 
Pathology 
X 
 
 
 
 
 
 
 
 
 
 
 
CT (CAP) 
X 
 
 
 
 
 
 
 
 
 
X 
X 
CEA 
X 
 
 
 
 
 
 
 
 
 
 
 
Endoscopy  
X 
 
 
 
 
 
 
 
 
 
 
 
B-HCG 
Xb 
 
 
 
 
 
 
 
 
 
 
 
Optional tumor 
biopsy 
Xd 
 
X 
X 
 
 
 
 
 
 
 
 
PKs 
 
X 
X 
 
 
 
 
 
 
 
 
 
Research blood 
draw 
X 
 
X 
X 
 
 
 
 
 
 
X 
 
  
A: AZD6244:  Dose as assigned; po BID dailyB: Capecitabine,  Dose  825 mg/m2 po every 12 hours, Monday- Friday (2 hours prior to radiation and 12 hours after 
first dose) 
C Radiotherapy: daily Monday- Friday 
 
a  Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, phosphorus, potassium, total protein, SGOT [AST], 
SGPT [ALT], sodium. 
b: Serum pregnancy test (women of childbearing potential). 
c: Off-study evaluation.  
d:  If sufficient tissue is available for pretreatment correlative work from the initial diagnostic biopsy this procedure will not be performed.  
e. Opthalmologic evaluation will be repeated in the event of any visual change or visual event due to AZD6244. 
f.  Baseline ophthalmologic and surgical consultation should be obtained within 3 weeks of beginning protocol therapy. 
g. RTOG scoring only 
h. Week 11 is pre- surgery 
i.  EKG will be obtained on Day 1 (2 hours after first AZD6244 dose), Day 8, week 4 and in the case of a cardiorespiratory AE. 
 
 
11. 
MEASUREMENT OF EFFECT 
Although response is not the primary endpoint of this trial, patients with measurable disease will 
be assessed by standard criteria.  For the purposes of this study, patients should be re-evaluated 


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at week 11 just prior to surgical therapy.  After surgical therapy, only recurrence will be 
documented.  Surgical and pathologic findings will be used to confirm response assessment at 11 
weeks. 
 
11.1 
Antitumor Effect – Solid Tumors 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee 
(version 1.1)  [Eur J Cancer. 2009 Jan;45(2):228-47].Changes in only the largest diameter 
(unidimensional measurement) of the tumor lesions are used in the RECIST criteria. 
 
11.1.1 Definition 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their 
first treatment with AZD6244. 
 
Evaluable for objective response.  Only those patients who have measurable disease 
present at baseline, have received a complete treatment, and have had their disease re-
evaluated will be considered evaluable for response.  These patients will have their 
response classified according to the definitions stated below.  (Note:  Patients who exhibit 
objective disease progression prior to the end of treatment will also be considered 
evaluable.) 
 
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 with 
conventional techniques (x-ray) or as >10 mm with spiral CT scan or caliper 
measurements by clinical exam.  Lymph nodes must be >15 mm in short axis by CT to be 
considered measurable (for lymph nodes only short axis will be followed).  All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters). 
 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with short axis < 15 mm are 
considered non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonis, inflammatory breast disease, 
abdominal masses (not followed by CT or MRI), and cystic lesions are all non-
measurable. 
 
Target lesions.  All measurable lesions up to a maximum of 5 lesions per organ and 10 
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) and their suitability for accurate 
repeated measurements (either by imaging techniques or clinically).  A sum of the longest 
diameter (LD) for all target lesions will be calculated and reported as the baseline sum 
LD.  The baseline sum LD will be used as reference by which to characterize the 
objective tumor response. 
 
Non-target lesions.  All other lesions (or sites of disease) including any measurable 


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lesions over and above the 10 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 or absence 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 when both methods have 
been used to assess the antitumor effect of a treatment. 
 
Clinical lesions
 
  Clinical lesions will only be considered measurable when they are 
superficial and > 10 mm in diameter (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
 
  These techniques should be performed with cuts of 5 mm 
or less in slice thickness contiguously.  This applies to tumors of the chest, abdomen, 
and pelvis.  Head and neck tumors and those of extremities usually require specific 
protocols.  MRI is acceptable in certain situations. 
Ultrasound (US)
 
 When the primary endpoint of the study is objective response 
evaluation, US should not be used to measure tumor lesions.  It is, however, a 
possible alternative to clinical measurements of superficial palpable lymph nodes, 
subcutaneous lesions, and thyroid nodules.  US might also be useful to confirm the 
complete disappearance of superficial lesions usually assessed by clinical 
examination. 
Endoscopy, Laparoscopy  The utilization of these techniques for objective tumor 
evaluation has not yet been fully and widely validated.  Their uses in this specific 
context require sophisticated equipment and a high level of expertise that may only be 
available in some centers.  Therefore, the utilization of such techniques for objective 
tumor response should be restricted to validation purposes in reference centers. 
However, such techniques may be useful to confirm complete pathological response 
when biopsies are obtained. 
 
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 in complete clinical response.  Specific additional criteria for standardized 
usage of prostate-specific antigen (PSA) and CA-125 response in support of clinical 


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trials are being developed. 
 
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. 
 
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. 
 
Partial Response (PR): At least a 30% decrease in the sum of the longest diameter 
(LD) of target lesions, taking as reference the baseline sum LD 
 
Progressive Disease (PD): At least a 20% increase in the sum of the LD of target 
lesions, taking as reference the smallest sum LD recorded since the treatment 
started or the appearance of one or more new lesions 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum LD since the 
treatment started 
 
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 (<10mm 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. 
 
Incomplete Response/Stable Disease (SD): 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 
 
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 


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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. 
 
 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
* 
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. 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and 
NE = inevaluable. 
 
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 recurrent 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.  
 
11.1.6 Progression-Free Survival 
PFS is defined as the duration of time from start of treatment to time of progression. 
 
11.2 
Other Response Parameters 
Pathologic complete response will be assessed on surgical specimens.  This will include an 
evaluation of evidence of residual gross and microscopic disease in the resected rectum and 


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lymph nodes.   
 
 
12. DATA REPORTING / REGULATORY REQUIREMENTS 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
 
12.1   Data Reporting 
 
 
12.1.1 Method 
This study will be monitored by the Clinical Data Update System (CDUS) version 3.0.  
Cumulative CDUS data will be submitted quarterly to CTEP by electronic means.  
Reports are due January 31, April 30, July 31 and October 31.  Instructions for submitting 
data using the CDUS can be found on the CTEP web site 
(http://ctep.cancer.gov/reporting/cdus.html). 
 
Note:  All adverse events that have occurred on the study, including those reported 
through AdEERS, must be reported via the monitoring method identified above. 
 
12.1.2 Responsibility for Data Submission 
N/A 
 
12.2 
Cooperative Research and Development Agreement (CRADA)/Clinical Trials 
Agreement (CTA) 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is 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/industry) 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 investigational 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 investigational 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 


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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 
NIH, 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 investigational 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 investigational Agent. 
 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative 
Agreement will be made available exclusively to Collaborator(s), the NCI, and 
the FDA, as appropriate and unless additional disclosure is required by law or 
court order.  Additionally, all Clinical Data and Results and Raw Data will be 
collected, used, and disclosed consistent with all applicable federal statutes and 
regulations for the protection of human subjects including, if applicable, the 
Standards for Privacy of Individually Identifiable Health Information set forth in 
45 C.F.R. Part 164. 
 
4. When a Collaborator wishes to initiate a data request, the request should first be 
sent to the NCI, who will then notify the appropriate investigators (Group Chair 
for Cooperative Group studies, or PI for other studies) of Collaborator's wish to 
contact them. 
 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance 
with the guidelines and policies of the responsible Data Monitoring Committee 
(DMC), if there is a DMC for this clinical trial. 
 
6. Any manuscripts reporting the results of this clinical trial must be provided to 
CTEP by the Group office for Cooperative Group studies or by the principal 
investigator for non-Cooperative Group studies for immediate delivery to 
Collaborator(s) for advisory review and comment prior to submission for 
publication.  Collaborator(s) will have 30 days from the date of receipt for review.  
Collaborator shall have the right to request that publication be delayed for up to 
an additional 30 days in order to ensure that Collaborator’s confidential and 
proprietary data, in addition to Collaborator(s)’s intellectual property rights, are 
protected.  Copies of abstracts must be provided to CTEP for forwarding to 
Collaborator(s) for courtesy review as soon as possible and preferably at least 


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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: 
 
Regulatory Affairs Branch, CTEP, DCTD, NCI 
Executive Plaza North, Suite 7111 
Bethesda, Maryland  20892 
FAX 301-402-1584 
Email: anshers@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. 
 
 
13. STATISTICAL CONSIDERATIONS 
 
13.1 Study Design/Endpoints 
This is a Phase I trial in which patients will be treated with escalating doses of AZD6244.  
There will be no intrapatient dose escalation.  The primary endpoints will be the MTD and 
the DLT’s.  The dose-escalation will proceed in cohorts of 3-6 patients at each dose level.  If 
0/3 experience DLT, the next cohort starts one dose level higher.  If 1/3 experience DLT, up 
to 3 more patients are started at that same dose level.  If 2 or more experience DLT, no 
further patients are started at that dose.  In the event that 2 or more patients of the first three 
enrolled at dose level 1 develop a DLT, de-escalation to dose level -1 will occur.  The MTD 
or recommended Phase II dose is the dose level at which no more than 1 of 6 patients 
experience DLT during treatment and the three weeks after completion. Six additional 
patients will be treated at the recommended phase II dose in order to refine toxicity 
assessment and obtain reasonable amounts of biologic data. 
 
The dose escalation will proceed only for AZD6244 while capecitabine and radiation doses 
remain constant.  The schema for escalation is as follows: 
 
 
Dose Escalation Schedule 
Dose Level 
Dose 
 
AZD6244 
 
Capecitabine 
 
Radiation* 
 
Level -1 
 
50 mg PO QD 
Weeks 1-7 
 
825 mg/m2 PO every 
12 hours 
Weeks 2-7 
 
5040 cGy 
Weeks 2-7 
 
Level 1 
 
50 mg PO BID 
Weeks 1-7 
 
825 mg/m2 PO every 
12 hours 
Weeks 2-7 
 
5040 cGy 
Weeks 2-7 
 
Level 2 
 
75 mg PO BID 
Weeks 1-7 
 
825 mg/m2 PO every 
12 hours 
 
5040 cGy 
Weeks 2-7 


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Weeks 2-7 
* An additional 360 cGy may be delivered for fixed T4 tumors for a total dose of 5400 cGy 
 
Toxicity will be scored according to the CTCAE v4.0 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev4.pdf).  
Dose-limiting toxicities will be defined as follows (during treatment and within the first three 
weeks after treatment) 
1.  Recurring and persistent Grade 3 diarrhea despite appropriate medical therapy.  
2.  ANC <500 for more than 5 days or neutropenic fever  
3.  Grade 4 thrombocytopenia 
4.  Recurring and persistent Grade 3 nausea/vomiting despite appropriate anti-emetic 
therapy 
5.  Grade 4 dermatitis acneiform rash 
6.  Grade 4 fatigue 
7.  All other non-hematologic toxicities of grade 3 or higher except electrolyte 
abnormalities that are correctable 
8.  Delays in radiation treatment due to toxicity of more than 2 weeks (cumulative 
duration over the course of the entire treatment). 
 
Toxicities should be attributable (possible, probable or definite) to the AZD6244, 
Capecitabine, and RT to constitute DLT. Patients who develop a DLT will continue 
Capecitabine and radiation after resolution or partial resolution of the DLT as 
clinically appropriate, and dose reduction of AZD6244 will occur as in section 5.1. 
 
 
 
13.2 
Sample Size/Accrual Rate 
The planned sample size is a minimum of 4 and a maximum of 18.  The estimated accrual is 
two patients per month. 
 
 
13.3 
Analysis of Secondary Endpoints 
The secondary endpoints include pathologic CR at the time of surgical resection, pERK/total 
ERK in PBMC and tumor, plasma TGFα level, pharmacokinetics of AZD6244 alone 
compared to in combination with capecitabine, and presence of mutations in tumor biopsies.  
Analysis of secondary endpoints will focus on samples obtained at the MTD (12 patients) 
with the goal of describing potentially useful measures for future testing in Phase II trials of 
sufficient power.  Changes in TGFα level from pre to post treatment will be related to the 
probability of pathologic CR using logistic regression.  Presence of activating BRAF or RAS 
mutations or inactivating PTEN mutations in tumor biopsies pretreatment will be related to 
the probability of pathologic CR using logistic regression.  We will evaluate if a reduction in 
pERK in PBMC (flow cytometry) correlates to a reduction in pERK in tumor (IHC grading) 
after AZD6244 treatment with a Spearman Rank Correlation. 
 
The final PK analyses will be the responsibility of Clinical Pharmacology and DMPK, 
Alderley Park, AstraZeneca, UK. The AZD6244, N-desmethyl and AZD6244 amide 
concentration-time data, along with the derived PK parameters, will be listed and 
summarized appropriately.  Where data allow, the following PK parameters will be 


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determined following administration of AZD6244 alone and following administration of 
AZD6244 alone and AZD6244 & capecitabine together. Additional parameters may be 
determined if deemed appropriate: 
 
AZD6244: Cmax, tmax, AUC(0-12), AUC(0-24), AUC(0-t), Cmin, CL/F 
 
N-desmethyl AZD6244 and AZD6244 amide: Cmax, tmax, AUC(0-12), AUC(0-24), AUC(0-t), Cmin, 
CL/F, AUC metabolite:parent ratio, Cmax metabolite:parent ratio 
 
The PK parameters will be derived using non-compartmental analysis. The maximum plasma 
concentrations (Cmax) and the time to reach the maximum plasma concentrations (tmax) will be 
determined by visual inspection of the plasma concentration-time profiles. The area under the 
plasma concentration-time curve from zero to 12 hours post dose AUC(0-12) and zero to 24 
hours post-dose AUC(0-24) will be calculated by the linear trapezoidal rule. The total oral 
clearance from plasma (CL/F) after an oral dose will be calculated from the dose divided by 
the AUC during the appropriate dosing interval.   
 
 
 
 


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Schmitz KJ, Wohlschlaeger J, Alakus H, et al. Activation of extracellular regulated kinases (ERK1/2) but 
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Arch 2007;450:151-159. 
 
  


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


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 68 
 
APPENDIX B 
 
New York Heart Association Classifications 
 
Clinical Evaluation of Functional Capacity of Patients 
with Heart Disease in Relation to Ordinary Physical Activity 
 
 
 
 
Class 
 
 
Cardiac Symptoms 
 
 
Limitations 
 
Need for 
Additional Rest* 
 
Physical Ability  
      to work**__ 
 
 
 
 
 
I 
None 
None 
None 
Full time 
 
 
 
 
 
II 
Only moderate 
Slight 
Usually only slight 
or occasional 
Usually full  
time 
 
 
 
 
 
III 
Defined, with  
less than  
ordinary activity 
Marked 
Usually moderate 
Usually part  
time 
 
 
 
 
 
IV 
May be present  
even at rest,  
and any activity 
increases discomfort 
Extreme 
Marked 
Unable to work 
 
 
* 
To control or relieve symptoms, as determined by the patient, rather than as advised by the 
physician. 
 
** At accustomed occupation or usual tasks. 
 
 
 
Reference: 
Bruce, R. A.: Mod. Concepts Cardiovasc. Dis. 25:321, 1956.  
 
 (Modified from New York Heart Association, 1953). 
 


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 69 
APPENDIX C 
MEDICATIONS THAT MAY CAUSE QTc PROLONGATION 
The following table presents a list of drugs that may prolong the QTc.  These drugs are prohibited during the 
study.  AZD 6244 may be administered after a 5 half-life washout period elapses following the use of these 
drugs.  Washout period is based on roughly 5 half-lives and rounded to a convenient interval.  
 
 
Compound 
 
Compound Half Life 
Possible 
Washout Period 
- Hours 
Possible 
Washout 
Period - Days 
Alfuzocin 
~10 hours 
 
7 
Amantadine 
17 +/- 4 hours (10-25) 
 
4 
Amiodarone (cordarone) 
58 days (15-142) 
36 days (active metabolite) 
 
180 
Amitriptyline* 
> 24 hours, wide interpatient variability 
 
 
Arsenic trioxide 
Not characterized 
 
 
Azithromycin 
40 hours 
 
 
Bepridil 
42 hr (26-64) 
 
10 
Chloral hydrate 
Readily converted to Trichloroethanol (active 
metabolite T1/2=7-10 hour) 
48 
 
Chloroquine 
Prolonged (days to weeks) 
 
 
Chlorpromazine 
30 +/- 7 hours 
 
7 
Cisapride 
6 – 12 hour, up to 20 hour 
60 
 
Clarithromycin 
Non linear PK3-4 hr (250mg Q12) 
5-7 hr (500mg Q12) 
36 
 
Cloroquine 
6 to 60 days; mean 20 days 
 
 
Desipramine* 
> 24 hours, wide interpatient variability 
 
 
Disopyramide 
6.7 hr (4-10) 
36 
 
Dofetilide 
10 hr 
48 
 
Dolesetron 
8.1 hr 
 
 
Domperidone 
7-8 hr 
48 
 
Doxepin* 
> 24 hours, wide interpatient variability 
 
 
Droperidol 
2.2 hours 
10 
 
Erythromycin 
* Each salt form has different Half life* 
 
 
Felbamate 
20-23 hr 
 
5 
Flecainide 
20 hr (12-27) 
 
5 
Foscarnet  
87.5+/-41.8 hours 
*distribution and release from bone* 
 
20 
Fosphenytoin 
12-29 hr 
 
6 
Gatifloxacin 
7-14 hr 
48 
 
Gemifloxacin 
7 hours 
48 
 
Grepafloxacin 
16 hr 
 
3 
Halofantrine 
6-10 days ( variable among individual) 
 
45 
Haloperidol 
18 +/-5 hr 
 
5 
Ibutilide 
6 hours (2-12) * variable among subject* 
36 
 
Imipramine* 
> 24 hours, wide interpatient variability 
 
 
Indapamide 
14 hours (biphasic elimination) 
 
3 
Isradipine 
8 hours ( multiple metabolites) 
48 
 
Levofloxacin 
6-8 hours 
48 
 
Levomethadyl 
Multiple compartment PK with active metabolite 
2.6 day for LAAM, 2 day for nor-LAAM, 4 day 
for dinor-LAAM 
 
20 
Lithium 
24 hour (10-50) 
 
7 


NCI PROTOCOL 10-C-0132 
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CTEP PROTOCOL # 8593                                          Version Date: October 24, 2011 
 
 
 70 
 
 
Compound 
 
Compound Half Life 
Possible Washout 
Period - Hours 
Possible 
Washout 
Period - Days 
Mesoridazine 
24-48 hours ( animal study) 
 
10 
Methadone 
15-30 hours 
 
7 
Moexipril/HCTZ 
2-9 hour (include active metabolite) for 
moexipril; 5.6-14.8 hours for HCTZ  
48 
 
Moxifloxacin 
12 +/-1.3 hours 
72 
 
Naratriptan 
6 hours 
36 
 
Nicardipine 
~ 2 hour post IV infusion 
12 
 
Nortriptyline* 
> 24 hours, wide interpatient variability 
 
 
Octreotide 
1.7 hours 
12 
 
Ofloxacin 
5 to 7.5 hours 
 
2 
Ondansetron 
4 hours (IV/IM); 3 hours (PO) 
 
1 to 3 
Pentamidine 
6.4+/-1.3 hours 
36 
 
Pimozide 
55 hours 
 
10 
Procainamide 
3-4 hour for PA and NAPA (active metabolite) 
24 
 
Protiptyline* 
> 24 hours, wide interpatient variability 
 
 
Quetiapine 
6 hours 
36 
 
Quinidine 
6-8 hours in adult; 3-4 hours in children 
36 
 
Quinine 
4-5 hours 
 
 
Risperidone 
3-20 hours (extensive to poor metabolizer) 
9-hydroxyrisperidone (active metabolite) T ½ 
=21-30 hours (extensive to poor metabolizer) 
 
4 
Salmeterol 
5.5 hours ( only one datum) 
36 
 
Sotalol 
12 hours 
72 
 
Sparfloxacin 
20 hours (16-30) 
 
4 
Sumatriptan 
2.5 hours 
12 
 
Tacrolimus 
~34 hours in healthy; ~19 hours in Kidney 
transplant 
 
7 
Tamoxifen 
5-7 days (biphasic) 
 
30 
Telithromycin 
2-3 hr 
24 
 
Thioridazine 
20-40 hours (Phenothiazines) 
 
7 
Tizanidine 
2.5 hours 
12 
 
Vardenifil 
4 to 5 hours 
 
 
Venlaflaxine 
5 +/-2 hours for parent comp. 
11+-2 hours for OVD (active metabolite) 
60 
 
Voriconizole 
6 hours; dose dependent 
 
 
Ziprasidone 
7 hr 
36 
 
Zolmitriptan 
2.8-3.7 hours (higher in female) 
18 
 
 
* Weakly associated with Torsades de Pointes and/or QT prolongation but that are unlikely to be a risk for Torsades de Pointes 
when used in usual recommended dosages and in patients without other risk factors (e.g., concomitant QT prolonging drugs, 
bradycardia, electrolyte disturbances, congenital long QT syndrome, concomitant drugs that inhibit metabolism). 
   
 
 References: 
1. 
Physician’s Desk Reference 2002 
2. 
Facts and Comparisons ( update to June 2005) 
3. 
The Pharmacological Basis of Therapeutics 9th Edition, 1996 


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 71 
APPENDIX D:  Patient’s Medication Diary      
 
 
Patient name_____________________________                                                                                     Page 1 of 2 
 
INSTRUCTIONS TO THE PATIENT: 
1.  Complete this form for both AZD6244 and Capecitabine. 
2.  You must take AZD6244 on an empty stomach with water only, either 1 hour before or two hour 
after meals.  Capecitabine should be taken two hours before radiation with food. 
3.  Record the date, the number of pills you took, and when you took them.   
4.  If you have any comments or notice any side effects, please record them in the Comments 
column. 
3.  Please bring this form to your physician when you go for your weekly appointment. 
4.  Total dose of AZD6244: ___mg ____ times per day.  Total number of pills at each dose: ___. 
5.  Total dose of capecitabine:_____mg two times per day.  ____ 150 mg pills and ____500 mg pills 
at each dose. 
 
AZD6244 
Capecitabine 
150 mg 
Capecitabine 
500 mg 
Comments 
Date 
Day 
# pills, 
when 
taken 
# of 
pills 
missed 
# pills, 
when 
taken 
# of 
pills 
missed 
# pills, 
when 
taken 
# of 
pills 
missed 
 
 
1 
 
 
 
 
 
Capecitabine is not taken  
on these days  
 
 
2 
 
 
 
 
3 
 
 
 
 
4 
 
 
 
 
5 
 
 
 
 
6 
 
 
 
 
7 
 
 
 
 
8 
 
 
 
 
 
 
 
 
9 
 
 
 
 
 
 
 
 
10 
 
 
 
 
 
 
 
 
11 
 
 
 
 
 
 
 
 
12 
 
 
 
 
 
 
 
 
13 
 
 
Capecitabine is not taken 
on these days 
 
 
14 
 
 
 
 
15 
 
 
 
 
 
 
 
 
16 
 
 
 
 
 
 
 
 
17 
 
 
 
 
 
 
 
 
18 
 
 
 
 
 
 
 
 
19 
 
 
 
 
 
 
 
 
20 
 
 
Capecitabine is not taken 
on these days 
 
 
21 
 
 
 
 
Patient’s signature________________________________________   Date_______________ 
 
 
 


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 72 
Patient name_____________________________                                                           Page 2 of 2 
 
INSTRUCTIONS TO THE PATIENT: 
1. 
Complete this form for both AZD6244 and Capecitabine. 
2. 
You must take AZD6244 on an empty stomach with water only, either 1 hour before or 
two hour after meals.  Capecitabine should be taken two hours before radiation and with 
food. 
3. 
Record the date, the number of pills you took, and when you took them.   
4. 
If you have any comments or notice any side effects, please record them in the 
Comments column. 
3. 
Please bring this form to your physician when you go for your weekly appointment. 
4.   Total dose of AZD6244: ___mg ____ times per day.  Number of pills at each dose: ___. 
5.  Total dose of capecitabine:_____mg two times per day.  ____ 150 mg pills and ____500 
mg pills at each dose. 
 
AZD6244 
Capecitabine 150 
mg 
Capecitabine 500 
mg 
Comments 
Date 
Day 
# pills, 
when 
taken 
# of 
pills 
missed 
# pills, 
when 
taken 
# of 
pills 
missed 
# pills, 
when 
taken 
# of 
pills 
missed 
 
 
22 
 
 
 
 
 
 
 
 
23 
 
 
 
 
 
 
 
 
24 
 
 
 
 
 
 
 
 
25 
 
 
 
 
 
 
 
 
26 
 
 
 
 
 
 
 
 
27 
 
 
Capecitabine is not taken 
on these days 
 
 
28 
 
 
 
 
29 
 
 
 
 
 
 
 
 
30 
 
 
 
 
 
 
 
 
31 
 
 
 
 
 
 
 
 
32 
 
 
 
 
 
 
 
 
33 
 
 
 
 
 
 
 
 
34 
 
 
Capecitabine is not taken 
on these days 
 
 
35 
 
 
 
 
36 
 
 
 
 
 
 
 
 
37 
 
 
 
 
 
 
 
 
38 
 
 
 
 
 
 
 
 
39 
 
 
 
 
 
 
 
 
40 
 
 
 
 
 
 
 
 
41 
 
 
Capecitabine is not taken 
on these days 
 
 
42 
 
 
 
 
43 
 
 
 
 
 
 
 
 
44 
 
 
 
 
 
 
 
 
45 
 
 
 
 
 
 
 
 
46 
 
 
 
 
 
 
 
 
47 
 
 
 
 
 
 
 
 
Patient’s signature________________________________________   Date_______________ 
 


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 73 
APPENDIX E:  Laboratory Correlative Studies Background 
Tumor mutational status – Laboratory Correlative Study #1 
The biopsy specimen will be obtained at the time of pretreatment endoscopy.  Biopsies will be collected, 
immediately placed in sterile saline on wet ice, and transported to the laboratory of Deborah Citrin.  
Specimens will centrifuged to remove supernatant and frozen at -80 C until transfer to the Laboratory of 
Pathology.  Evaluation for mutations will be performed by the Laboratory of Pathology at the NCI which 
completes these assays as standard practice on tumor samples.  If additional DNA or tissue remains and 
PTEN expression is absent by immunohistochemistry, pcr for amplification of PTEN exons followed by 
sequencing will occur in the laboratory of Dr. Deborah Citrin. 
 
Tumor ERK1/2 phosphorylation and PTEN expression – Laboratory Correlative Study #2) 
The specimen will be collected at the time of pretreatment endoscopy and on day 8 and day 15. The 
specimen will be submitted in formalin for processing and imunohistochemistry.  Immunohistochemistry 
will be performed with chromagen based detection using a polyclonal primary antibody directed against 
phospho-ERK1/2.(45, 46)  If additional sample is available tumor PTEN expression will be evaluated 
with immunohistochemistry. 
 
Peripheral mononuclear cell ERK1/2 phosphorylation and pharmacokinteics – Laboratory Correlative 
Study #3) 
Collection of Specimen:  A whole blood specimen will be collected pretreatment, day 8, day 15, and at 
one month of follow up.  Whole blood will be collected and transported immediately to the laboratory of 
Deborah Citrin for processing for flow cytometric analysis.  The technique used for processing and 
analysis will be identical to that used by Astra Zeneca in prior trials of AZD6244. 
PBMC and plasma samples will also be collected on days 4-5 and days 11-12 for pharmacokinetic and 
pharmacodynamic analysis.  Collection of specimen:  3 mL of whole blood will be sampled at the time 
points indicated below.  Blood will be immediately transported to the laboratory of Deborah Citrin for 
processing and storage prior to shipment in batches to Astra Zeneca.   
For QD dosing these samples will be obtained at ): Pre-dose (within 10 minutes of dosing), 30 minutes, 1 
hour, 1 hour 30 minutes, 2, 4, 8, 12 and 24 hours post-dose (24 hour sample is pre- the next day’s dose).  
Day 11 or 12 (AZD6244 + capecitabine + radiotherapy): Pre-dose (within 10 minutes of dosing), 30 
minutes, 1 hour, 1 hour 30 minutes, 2, 4, 8, 12 and 24 hours post-dose (24 hour sample is pre- the next 
day’s dose).   
For BID dosing these samples will be obtained at Day 4 or 5 (AZD6244 alone): Pre-dose (within 10 
minutes of dosing), 30 minutes, 1 hour, 1 hour 30 minutes, 2, 4, 8 and 12 hours post-dose (12 hour sample 
is pre- the next day’s dose).  Day 11 or 12 (AZD6244 + capecitabine + radiotherapy): Pre-dose (within 10 
minutes of dosing), 30 minutes, 1 hour, 1 hour 30 minutes, 2, 4, 8 and 12 hours post-dose (12 hour sample 
is pre- the next day’s dose). 
Plasma TGFα – Laboratory Correlative Study #4)Collection of Specimen:  Specimen will be collected 
pretreatment, day 8, day 15, and at one month of follow up.  Plasma will be immediately transported on 
ice to the laboratory of Deborah Citrin.  Plasma will be processed within 15 minutes of collection.  
Aliquots will be stored at -80 C until use.  TGF-α levels will be assessed with the commercially available 
Elisa kit from R&D Systems as per manufacturer’s instruction 


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 74 
APPENDIX F: ACUTE RTOG 
 
 
 
[ 0 
] 
[ 1 ] 
[ 2 ] 
[ 3 ] 
[ 4 ] 
SKIN 
No change 
over 
baseline 
Follicular, faint or dull erythema/ 
epilation/dry desquamation/ 
decreased sweating 
Tender or bright erythema, patchy 
moist desquamation/ moderate 
edema 
Confluent, moist desquamatiom other than skin folds, 
pitting edema 
Ulceration, hemorrhage, necrosis 
UPPER G.I. 
No change 
Anorexia with <=5% weight loss 
from pretreatment baseline/ nausea 
not requiring antiemetics/ abdominal 
discomfort not requiring 
parasympatholytic drugs or 
analgesics 
Anorexia with <=15% weight loss 
from pretreatment baseline/nausea 
&/ or vomiting requiring 
antiemetics/ abdominal pain 
requiring analgesics 
Anorexia with >15% weight loss from pretreatment 
baseline or requiring N-G tube or parenteral support. 
Nausea &/or vomiting requiring tube or parenteral 
support/abdominal pain, severe despite 
medication/hematemesis or melena/ abdominal distention 
(flat plate radiograph demonstrates distended bowel loops 
Ileus, subacute or acute obstruction, 
performation, GI bleeding requiring 
transfusion/abdominal pain requiring 
tube decompression or bowel diversion 
LOWER G.I. 
INCLUDING 
PELVIS 
No change 
Increased frequency or change in 
quality of bowel habits not requiring 
medication/ rectal discomfort not 
requiring analgesics 
Diarrhea requiring 
parasympatholytic drugs (e.g., 
Lomotil)/ mucous discharge not 
necessitating sanitary pads/ rectal 
or abdominal pain requiring 
analgesics 
Diarrhea requiring parenteral support/ severe mucous or 
blood discharge necessitating sanitary pags/abdominal 
distention (flat plate radiograph demonstrates distended 
bowel loops) 
Acute or subacute obstruction, fistula 
or perforation; GI bleeding requiring 
transfusion; abdominal pain or 
tenesmus requiring tube decompression 
or bowel diversion 
GENITOURINARY 
No change 
Frequency of urination or nocturia 
twice pretreatment habit/ dysuria, 
urgency not requiring medication 
Frequency of urination or nocturia 
which is less frequent than every 
hour. Dysuria, urgency, bladder 
spasm requiring local anesthetic 
(e.g., Pyridium) 
Frequency with urgency and nocturia hourly or more 
frequently/ dysuria, pelvis pain or bladder spasm requiring 
regular, frequent narcotic/gross hematuria with/ without 
clot passage 
Hematuria requiring transfusion/ acute 
bladder obstruction not secondary to 
clot passage, ulceration or necrosis 
HEMATOLOGIC 
WBC (X 1000) 
>=4.0 
3.0 - <4.0 
2.0 - <3.0 
1.0 - <2.0 
<1.0 
PLATELETS (X 
1000) 
>=100 
75 - <100 
50 - <75 
25 - <50 
<25 or spontaneous bleeding 
NEUTROPHILS 
>=1.9 
1.5 - <1.9 
1.0 - <1.5 
0.5 - <1.0 
<0.5 or sepsis 
HEMOGLOBIN (GM 
%) 
>11 
11-9.5 
<9.5 - 7.5 
<7.5 - 5.0 
------- 
HEMATOCRIT (%) 
>=32 
28 - <32 
<28 
Packed cell transfusion required 
------- 
GUIDELINES: The acute morbidity criteria are used to score/grade toxicity from radiation therapy. The criteria are relevant from day 1, the commencement of therapy, through day 90. Thereafter, the EORTC/RTOG 
Criteria of Late Effects are to be utilized. 
 
The evaluator must attempt to discriminate between disease- and treatment-related signs and symptoms. 
 
An accurate baseline evaluation prior to commencement of therapy is necessary. 
 
All toxicities Grade 3, 4 or 5
* must be verified by the Principal Investigator. 
 
*ANY TOXICITY WHICH CAUSED DEATH IS GRADED 5. 
 


NCI PROTOCOL 10-C-0132 
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CTEP PROTOCOL # 8593                                          Version Date: October 24, 2011 
 
 
 75 
APPENDIX G: LATE RTOG TOXICITY 
 
[ 0 ] 
[ 1 ] 
[ 2 ] 
[ 3 ] 
[ 4 ] 
SKIN 
No change 
Slight atrophy 
Pigmentation change 
Some hair loss 
Patch atrophy; Moderate telangiectasia; 
Total hair loss 
Marked atrophy; Gross telangiectasia 
Ulceration 
SUBCUTANEOUS 
TISSUE 
No change 
Slight induration (fibrosis) and loss of 
subcutaneous fat 
Moderate fibrosis but asymptomatic 
Slight field contracture 
<10% linear reduction 
Severe induration and loss of 
subcutaneous tissue 
Field contracture 
>10% linear measurement 
Necrosis 
SMALL/LARGE 
INTESTINE 
No change 
Mild diarrhea 
Mild cramping 
Bowel movement 5 times daily 
Slight rectal discharge or bleeding 
Moderate diarrhea and colic 
Bowel movement >5 times daily 
Excessive rectal mucus or intermittent 
bleeding 
Obstruction or bleeding 
requiring surgery 
Necrosis/ Perforation 
Fistula 
BLADDER 
No change 
Slight epithelial atrophy 
Minor telangiectasia (microscopic 
hematuria) 
Moderate frequency 
Generalized telangiectasia 
Intermittent macroscopic hematuria 
Severe frequency and dysuria 
Severe generalized telangiectasia (often 
with petechiae) 
Frequent hematuria 
Reduction in bladder capacity (<150 cc) 
Necrosis/ Contracted bladder 
(capacity <100 cc) 
Severe hemorrhagic cystitis 
BONE 
No change 
Asymptomatic 
No growth retardation 
Reduced bone density 
Moderate pain or tenderness 
Growth retardation 
Irregular bone sclerosis 
Severe pain or tenderness 
Complete arrest of bone growth 
Dense bone sclerosis 
Necrosis/ Spontaneous fracture 
JOINT 
No change 
Mild joint stiffness 
Slight limitation of movement 
Moderate stiffness 
Intermittent or moderate joint pain 
Moderate limitation of movement 
Severe joint stiffness 
Pain with severe limitation of movement 
Necrosis/ Complete fixation 
GUIDELINES: The late morbidity criteria are used to score/grade toxicity from radiation therapy. The critera are relevant beginning at day 90 after therapy. 
 
The evaluator must attempt to discriminate between disease- and treatment-related signs and symptoms. 
 
An accurate baseline evaluation prior to commencement of therapy is necessary. 
 
All toxicities Grade 3, 4 or 5
* must be verified by the Principal Investigator. 
 
*ANY TOXICITY WHICH CAUSED DEATH IS GRADED 5. 
 
 
 
 
 
 

ICF_001.pdf: 
 
 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
   MEDICAL RECORD 
               •  Adult Patient or     •  Parent, for Minor Patient 
 
 
INSTITUTE: 
 
National Cancer Institute 
 
 
STUDY NUMBER: 
10-C-0132 
PRINCIPAL INVESTIGATOR:  Deborah Citrin, M.D. 
 
 
STUDY TITLE: 
A Phase I Study of AZD6244 in Combination with Capecitabine and Radiotherapy in Locally 
Advanced Adenocarcinoma of the Rectum 
 
 
Initial Review Approved by the IRB on 02/28/11 
Amendment Approved by the IRB on 10/27/11 (F) 
 
 
 
Date Posted to Web:  11/15/11 
Standard 
 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL 
 
RESEARCH STUDY 
 
•   Adult Patient or    •   Parent, for Minor Patient 
 
NIH-2514-1 (07-09) 
 
P.A.: 09-25-0099 
 
File in Section 4:  Protocol Consent (1) 
 
 
INTRODUCTION 
 
We invite you to take part in a research study at the National Institutes of Health (NIH). 
 
First, we want you to know that: 
 
 
Taking part in NIH research is entirely voluntary. 
 
 
You may choose not to take part, or you may withdraw from the study at any time.  In either case, you will not 
lose any benefits to which you are otherwise entitled.  However, to receive care at the NIH, you must be taking 
part in a study or be under evaluation for study participation. 
 
 
You may receive no benefit from taking part.  The research may give us knowledge that may help people in the 
future. 
 
Second, some people have personal, religious or ethical beliefs that may limit the kinds of medical or research treatments 
they would want to receive (such as blood transfusions).  If you have such beliefs, please discuss them with your NIH 
doctors or research team before you agree to the study. 
 
Now we will describe this research study.  Before you decide to take part, please take as much time as you need to ask 
any questions and discuss this study with anyone at NIH, or with family, friends or your personal physician or other 
health professional. 
 
Why is this study being done?  
The purpose of this study is to find out what effects, good and/or bad, AZD6244 has on you and your rectal cancer.  In 
some types of cancer such as yours, a protein called MEK is over active.  This protein is important for cancer cells to be 
able to reproduce and survive.  Because AZD6244 prevents MEK from working properly, it may keep your cancer cells 
from growing and living, so your cancer may shrink or its growth may slow down.  In addition, it is possible that MEK can 
help tumor cells survive radiation treatments.  Using AZD6244 may allow radiation to kill more tumor cells by preventing 
MEK from working properly.  AZD6244 is an investigational or experimental anti-cancer agent that has not been approved 
by the Food and Drug Administration for use in patients with rectal cancer. 
 


 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
10-C-0132 
CONTINUATION:  page  2  of  10  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
Why are you being asked to take part in this study? 
You are being asked to take part in this study because you have rectal cancer that has spread outside the inner wall of 
the rectum or into lymph nodes in the pelvis that typically would require radiation and chemotherapy for treatment.  You 
are being asked to participate because we are studying if AZD6244 can be delivered with chemotherapy and radiation for 
patients with the type for tumor that you have. 
 
How many people will take part in this Study?  
About 12 people will take part in this study.  At the beginning of the study, patients will be treated with lower doses of 
the investigational drug.  If the drug does not cause bad side effects, the dose will slowly be made higher as new patients 
take part in the study.  The dose of AZD6244 will stay the same over the entire treatment for each patient.  All patients 
will receive similar doses of radiation and capecitabine, a type of chemotherapy drug commonly used in the treatment of 
rectal cancer.  A total of 18 patients are the most that would be able to enter the study.  
 
Description of Research Study 
What will happen if you take part in this research study?   
Before you begin the study, you will need to have the following exams, tests or procedures to find out if you can be in the 
study.  These exams, tests or procedures are part of regular cancer care and may be done even if you do not join the 
study.  If you have had some of them recently, they may not need to be repeated.  This will be up to your study doctor. 
• 
History and Physical examination 
• 
CT scan of the chest, abdomen, and pelvis 
• 
MRI or ultrasound of the rectal tumor 
• 
Basic laboratory tests including blood counts and measurement of kidney function, liver function, and 
electrolytes in the blood. 
• 
ECG (Electrocardiogram) 
 
If the exams, tests and procedures show that you can be in the study, and you choose to take part, then you will need 
the following tests and procedures.  They are part of regular cancer care.  
• 
Radiation treatment planning and daily radiation treatments for six weeks 
• 
Treatment with chemotherapy (capecitabine) taken as a pill during the radiation treatment 
• 
Blood tests every week to check blood cell counts, blood electrolytes, and blood chemistries. 
• 
Weekly visits with the radiation oncologist during treatment. 
• 
Weekly ECG 
 
You will need these tests and procedures that are either being tested in this study or being done to see how the study is 
affecting your body. 
• 
Treatment with AZD6244 
• 
Sampling of two tablespoons of blood during the first three weeks of treatment and at one month after 
treatment 
 
While you are in the study, you will need to keep track of the medicine you take with a medication diary.  You will be 
given a form for the medication diary, and you will write in it each day.  You will be treated with AZD6244 in addition to 
radiation, chemotherapy, and surgery which are the usual treatment for rectal cancer that has spread outside the rectum.  
This means that for one week before you start radiation and chemotherapy and during the rest of your treatment you will 
take AZD6244 capsules twice each day. 
 


 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
10-C-0132 
CONTINUATION:  page  3  of  10  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
When you are finished taking AZD6244, you will continue to be seen every few weeks by the radiation oncologist.  You 
will stop taking AZD6244 the same day you complete radiation and chemotherapy.  You will undergo repeated physical 
examination, blood testing, and x-rays to see how your tumor responds to treatment and to make sure surgery is safe.  
Four to eight weeks after completing the treatment with AZD6244, radiation, and capecitabine you should undergo 
surgery to remove the rectal tumor and any lymph nodes near the rectum.  This surgery is not part of the treatment 
delivered on this protocol.  You may be eligible to receive surgery at NIH on other protocols. 
 
You will be asked to take AZD6244 for approximately seven weeks including one week before your radiation and 
chemotherapy treatment and then continuing until the end of radiation and chemotherapy.  After you are finished taking 
AZD6244, the study doctor will ask you to visit the office for a follow-up exam three weeks after you finish treatment to 
make sure you are not having side effects from the treatment.  After treatment, you will also be asked to come for follow 
up visits every three months for the first year and then every year until you have been followed for three years.  At these 
visits your doctor will examine you and ask questions to try to determine if you have any side effects from your radiation 
treatment.  You will also need to have x-rays (CT scans) during these follow up visits to make sure that the tumor is 
gone. 
 
Study Chart 
Another way to find out what will happen to you during the study is to read the chart below.  Start reading at the top and 
read down the list, following the lines and arrows.  
 
 
 
 
                                                               
 
 
                                                                    
 
 
 
 
 
 
Radiation Treatment Simulation (planning session) 
Medicines used in this study 
AZD6244 given twice a day by mouth seven days per week for one week before starting radiation and chemotherapy 
and continuing until completion of radiation and chemotherapy 
Radiation given daily, Monday through Friday (5 days per week) starting one week after AZD6244 treatment starts for 
approximately 6 weeks 
Capecitabine given twice daily, Monday through Friday (5 days per week) starting one week after AZD6244 treatment 
starts for approximately 6 weeks 
Rest period for 4-8 weeks prior to surgery 
(surgery is not part of this study) 
     Enrollment on the study 


 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
10-C-0132 
CONTINUATION:  page  4  of  10  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
What does this study involve? 
 
Standard of Care Treatment: 
Treatments covered under this study may include capecitabine (a chemotherapy) and radiation to treat your cancer. 
These treatments will not be experimental. Your doctors will describe your treatment plan to you in detail before asking 
you to sign this consent form. You may be asked to sign a separate consent form for any treatment procedures not 
outlined in this consent. 
Birth Control 
If you are a woman who is breast feeding or pregnant, you may not take part in the study because we don’t know how 
this medicine would affect your baby or your unborn child. If you are a woman who can become pregnant, or are the 
partner of a woman who can become pregnant, you will need to practice an effective form of birth control before starting 
study treatment, during study treatment, and for 6 months after you finish study treatment.  If you think that you or your 
partner is pregnant, you should tell your study doctor or nurse at once.  
  
Effective forms of birth control include:  
• 
Abstinence  
• 
intrauterine device (IUD) 
• 
hormonal [birth control pills, injections, or implants] 
• 
tubal ligation 
• 
vasectomy 
 
Alternative Approaches or Treatments 
What other choices do I have if I do not take part in this study?  
 
Instead of being in this study, you have these options: 
• 
Getting treatment or care for your cancer without being in a study 
• 
Taking part in another study 
Please talk to your doctor about these and other options. 
 
Risks or Discomforts of Participation 
You may have side effects while on the study.  Everyone taking part in the study will be watched carefully for any side 
effects.  However, doctors don’t know all the side effects that may happen.  Side effects may be mild or very serious.  
Your health care team may give you medicines to help lessen side effects.  Many side effects go away soon after you stop 
taking the AZD6244.  In some cases, side effects can be serious, long lasting, or may never go away. 
 
What side effects or risks can I expect from being in this study? 
Possible side effects from AZD6244:  
Likely: 
• 
Diarrhea 
• 
Nausea or the urge to vomit 
• 
Vomiting 
• 
Swelling of the arms and/or legs 


 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
10-C-0132 
CONTINUATION:  page  5  of  10  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
• 
Fatigue or tiredness 
• 
Acne 
• 
Skin rash with the presence of macules (flat discolored area) and papules (raised bump) 
 
Less Likely: 
• 
Lack of enough red blood cells (anemia) 
• 
Belly pain 
• 
Constipation 
• 
Dry mouth 
• 
Irritation or sores in the lining of the mouth 
• 
Swelling of the face 
• 
Fever 
• 
Increased blood level of a liver enzyme (ALT/SGPT) 
• 
Increased blood level of a liver or bone enzyme (alkaline phosphatase) 
• 
Increased blood level of a liver enzyme (AST/SGOT) 
• 
Decreased number of a type of blood cell that helps to clot blood (platelet) 
• 
Loss of appetite 
• 
Decreased levels of a blood protein called albumin 
• 
Decreased blood level of magnesium 
• 
Dizziness (or sensation of lightheadedness, unsteadiness, or giddiness) 
• 
Headache or head pain 
• 
Difficulty sleeping or falling asleep 
• 
Cough 
• 
Shortness of breath 
• 
Dry skin 
• 
Itching 
• 
High blood pressure  
 
Rare but Serious: 
• 
Fever associated with dangerously low levels of a type of white blood cell (neutrophils) 
• 
Decrease in heart's ability to pump blood during the "active" phase of the heartbeat (systole) 
Capeciatabine and radiation are not experimental treatments for rectal cancer.  The possible side effects of capecitabine 
are listed below.  Your doctor will discuss these with you.  It is important to let your doctor know if you develop these 
side effects because adjustments to your treatment may need to be made. 
 
The most common side effects of capecitabine are: 
Diarrhea 
Nausea and/or vomiting 
Sores in the mouth and throat (stomatitis) 
Upset stomach 
Loss of appetite 
Fatigue 
Too much water loss from the body (dehydration) 
Painful tingling rash on the hands and feet 


 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
10-C-0132 
CONTINUATION:  page  6  of  10  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
Other types of rash 
Decrease in blood counts (especially white blood cell count) 
Itchy skin 
Hair loss 
Nail problems 
Tiredness or weakness 
Headache 
Fever 
Pain 
Trouble sleeping 
Changes in taste 
Pain (muscle, back, joint, chest) 
 
Some additional aide effects may occur with radiation to the pelvic area.  These side effects are listed below.  Your 
doctor will discuss these with you.  It is important to let your doctor know if you develop these side effects because 
changes may need to be made to your treatment.  The short term side effects of radiation tend to go away a few 
weeks after treatment is completed. 
 
Likely short term side effects of radiation 
Skin irritation in the area radiated (pelvis) 
Fatigue 
Diarrhea 
Hair loss in the area treated with radiation 
 
Less Likely short term side effects of radiation. 
Burning with urination or urgent urination 
Decrease in blood counts 
Pain in the pelvis area 
 
Some side effects of radiation can happen many months or years after treatment.  It is impossible to predict who will 
develop long term side effects.  Your doctor will discuss these risks with you.  The possible long term side effects of 
radiation to the pelvis can include: 
 
Common:  increased tendency to develop gas or diarrhea, more frequent or urgent bowel movements, infertility 
Uncommon:  bleeding from the rectum, bleeding from the bladder, scarring of the vagina in females, decreased 
sexual function in males 
Extremely rare:   injury to the hips that could result in a fracture of bone, life threatening tumor caused by radiation. 
 
Potential Benefits of Participation 
Are there benefits to taking part in this study? 
The aim of this study is to see if AZD6244 in combination with radiation and chemotherapy will cause your tumor to 
shrink.  We hope that you will get personal medical benefit from taking part in this study, but we cannot be certain.  
These potential benefits could include shrinking of your tumor or lessening of your symptoms, such as pain, that are 
caused by the cancer.  Because there is not much information about the drug’s effect on your cancer, we do not know if 
you will benefit from taking part in this study, although the knowledge gained from this study may help others in the 


 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
10-C-0132 
CONTINUATION:  page  7  of  10  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
future who have cancer.  While doctors hope AZD6244 will be more useful against cancer compared to the usual 
treatment, there is no proof of this yet.  We do know that the information from this study will help doctors learn more 
about AZD6244 as a treatment for cancer.  This information could help future cancer patients. 
 
Research Subject’s Rights 
What are the costs of taking part in this study?  
If you choose to take part in the study, the following will apply, in keeping with the NIH policy: 
• 
You will receive all treatment on this study at no charge to you. This may include surgery, 
medicines, laboratory testing, x-rays or scans done at the Clinical Center, National Institutes of 
Health (NIH), or arranged for you by the research team to be done outside the Clinical Center, 
NIH if the study related treatment is not available at the NIH.   Any medicine used as part of 
the study (AZD6244 and capecitabine) and medicines used to treat side effects of the study will 
be provided at no charge to you. 
• 
There are limited funds available to cover the cost of some tests and procedures performed 
outside the Clinical Center, NIH.  You may have to pay for these costs even if they are not 
covered by your insurance company. 
• 
Medicines that are not part of the study treatment will not be provided or paid for by the Clinical 
Center, NIH.  
• 
Once you have completed taking part in the study, medical care will no longer be provided by 
the Clinical Center, NIH. 
The National Cancer Institute and the Pharmaceutical Company (Astra-Zeneca) that makes AZD6244 may inspect and 
copy patient’s research records for quality assurance and data analysis. 
 
Stopping Therapy 
Your doctor may decide to stop your therapy for the following reasons: 
• 
if he/she believes that it is in your best interest 
• 
if your disease grows during treatment 
• 
if you have side effects from the treatment that your doctor thinks are too severe 
• 
if new information shows that another treatment would be better for you 
 
In this case, you will be informed of the reason therapy is being stopped.  If the investigational treatment is stopped, you 
may continue to receive chemotherapy and radiation to complete your treatment if the investigator thinks it is safe. 
You can stop taking part in the study at any time. However, if you decide to stop taking part in the study, we would like 
you to talk to the study doctor and your regular doctor first. 
 
Conflict of Interest 
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for conflicts of interest.  The 
following link contains details on this process http://ethics.od.nih.gov/procedures/COI-Protocol-Review-Guide.pdf.  You 
may ask your research team for a copy of the Protocol Review Guide or for more information.  Members of the research 
team who do not work for NIH are expected to follow these guidelines but they do not need to report their personal 
finances to the NIH. 
 


 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
10-C-0132 
CONTINUATION:  page  8  of  10  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
Members of the research team working on this study may have up to $15,000 of stock in the companies that make 
products used in this study.  This is allowed under federal rules and is not a conflict of interest.  
 
Optional Biopsy 
You are being given the option of having a biopsy before and twice during the course of your treatment. Your doctor will 
remove some small pieces of tumor from the rectum to do some research tests. This procedure will be performed under 
mild sedation if required so that you will be more comfortable during the procedure.  The results of these tests will not be 
used to plan your care. This tissue will be used to allow us to test the effects of AZD6244 on the tumor. 
The research that may be done with your tissue is not designed specifically to help you. It might help people who have 
cancer and other diseases in the future.  Reports about research done with your tissue will not be given to you or your 
doctor. These reports will not be put in your health record. The research will not have an effect on your care.  
The choice to undergo these biopsies is up to you. No matter what you decide to do, it will not affect your care. Your 
tissue will be used only for research and will not be sold. The research done with your tissue may help to develop new 
products in the future.   
The benefits of research using tissue include learning more about what causes cancer and other diseases, how to prevent 
them, and how to treat them.  We may also be able to tell better how AZD6244 affects tumors by looking at the biopsy 
tissue. Biopsies can result in pain that usually goes away within a day or two of the biopsy.  In addition, there is a small 
risk of infection or bleeding after the biopsy.  
 
Even if you sign "yes" to have the biopsy you can change your mind at any time.  Please read each sentence below and 
think about your choice. After reading each sentence, circle and initial the answer that is right for you. The decision to 
participate in this part of the research is optional, and no matter what you decide to do, it will not affect your care.   
 
I agree to have the tumor biopsy for the research tests in this study.  
 
Yes              No               Initials_________ 
 
Optional Studies 
We would like to keep some of the tissue, blood, and urine that are collected for future research.  These specimens will 
be identified by a number and not your name.  The use of your specimens will be for research purposes only and will not 
benefit you.  It is also possible that the stored specimens may never be used.  Results of research done on your 
specimens will not be available to you or your doctor.  It might help people who have cancer and other diseases in the 
future.   
 


 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
10-C-0132 
CONTINUATION:  page  9  of  10  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
If you decide now that your tissue, blood, and urine can be kept for research, you can change your mind at any time. 
Just contact us and let us know that you do not want us to use your tissue, blood, and urine.  Then any tissue, blood, 
and urine that remain will be destroyed.  
 
Please read each sentence below and think about your choice. After reading each sentence, circle and initial the answer 
that is right for you.  No matter what you decide to do, it will not affect your care. 
 
1. My tissue, blood, and urine specimens may be kept for use in research to learn about, prevent, or treat cancer.  
 
Yes              No               Initials_________ 
 
2. My specimens may be kept for use in research to learn about, prevent or treat other health problems (for example: 
diabetes, Alzheimer's disease, or heart disease).  
 
Yes              No               Initials_________ 
 
3. Someone may contact me in the future to ask permission to use my specimen(s) in new research not included in this 
consent.  
 
Yes              No               Initials_________ 
 
 


 
  
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
   MEDICAL RECORD 
•  Adult Patient or    •  Parent, for Minor Patient 
 
STUDY NUMBER: 
10-C-0132 
CONTINUATION:  page  10  of  10  pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL 
 
RESEARCH STUDY (Continuation Sheet) 
 
•  Adult Patient or   •  Parent, for Minor Patient 
 
NIH-2514-1 (07-09) 
 
P.A.: 09-25-0099 
 
File in Section 4:  Protocol Consent 
 
OTHER PERTINENT INFORMATION 
 
1. Confidentiality.  When results of an NIH research study are reported in medical journals or at scientific meetings, 
the people who take part are not named and identified.  In most cases, the NIH will not release any information about 
your research involvement without your written permission.  However, if you sign a release of information form, for 
example, for an insurance company, the NIH will give the insurance company information from your medical record.  This 
information might affect (either favorably or unfavorably) the willingness of the insurance company to sell you insurance. 
 
The Federal Privacy Act protects the confidentiality of your NIH medical records.  However, you should know that the Act 
allows release of some information from your medical record without your permission, for example, if it is required by the 
Food and Drug Administration (FDA), members of Congress, law enforcement officials, or authorized hospital 
accreditation organizations. 
 
2. Policy Regarding Research-Related Injuries.  The Clinical Center will provide short-term medical care for any 
injury resulting from your participation in research here.  In general, no long-term medical care or financial compensation 
for research-related injuries will be provided by the National Institutes of Health, the Clinical Center, or the Federal 
Government.  However, you have the right to pursue legal remedy if you believe that your injury justifies such action. 
 
3. Payments.  The amount of payment to research volunteers is guided by the National Institutes of Health policies.  In 
general, patients are not paid for taking part in research studies at the National Institutes of Health.  Reimbursement of 
travel and subsistence will be offered consistent with NIH guidelines. 
 
4. Problems or Questions.  If you have any problems or questions about this study, or about your rights as a 
research participant, or about any research-related injury, contact the Principal Investigator, Deborah Citrin, M.D., 
Building 10, CRC B2-3500, Telephone:  301-496-5457. If you have any questions about the use of your tissue for future 
research studies, you may also contact the Office of the Clinical Director, Telephone: 301-496-4251. 
 
You may also call the Clinical Center Patient Representative at 301-496-2626. 
 
5. Consent Document.  Please keep a copy of this document in case you want to read it again. 
 
COMPLETE APPROPRIATE ITEM(S) BELOW: 
 
A. Adult Patient’s Consent 
B. Parent’s Permission for Minor Patient. 
I have read the explanation about this study and have been given the 
opportunity to discuss it and to ask questions.  I hereby consent to take 
part in this study. 
I have read the explanation about this study and have been given the 
opportunity to discuss it and to ask questions.  I hereby give permission 
for my child to take part in this study.   
(Attach NIH 2514-2, Minor’s Assent, if applicable.) 
 
 
  
 
 
  
 
Signature of Adult Patient/Legal Representative 
Date 
 
 
 
Print Name 
Signature of Parent(s)/Guardian 
Date 
 
 
 
Print Name 
C. Child’s Verbal Assent (If Applicable) 
The information in the above consent was described to my child and my child agrees to participate in the study. 
 
 
 
  
 
 
 
 
Signature of Parent(s)/Guardian 
Date 
 
Print Name 
THIS CONSENT DOCUMENT HAS BEEN APPROVED FOR USE  
FROM FEBRUARY 28, 2011 THROUGH FEBRUARY 27, 2012.  
 
 
 
  
 
 
  
 
Signature of Investigator 
Date 
 
 
 
Print Name 
Signature of Witness 
Date 
 
 
 
Print Name