Clinical trial NCT01239342
Conditions: Metastatic Kidney Carcinoma Recurrent Renal Cell Carcinoma Stage III Renal Cell Cancer AJCC v7 Stage IV Renal Cell Cancer AJCC v7
Sponsor: National Cancer Institute (NCI)
Start date: 2011-01-27; Completion date: 2018-09-19
Enrollment: 43 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This randomized phase II trial studies the side effects and how well Akt inhibitor MK2206 or everolimus works in treating patients with kidney cancer that does not respond to treatment. Akt inhibitor MK2206 and everolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Everolimus may also stop the growth of kidney cancer by blocking blood flow to the tumor. It is not yet known whether Akt inhibitor MK2206 or everolimus is more effective in treating kidney cancer.

Detailed description:
PRIMARY OBJECTIVES:

I. To assess progression free survival (PFS) of vascular endothelial growth factor (VEGF) therapy refractory renal cell carcinoma (RCC) patients who receive either MK-2206 (Akt inhibitor MK-2206) or everolimus.

II. To assess safety of MK-2206 in patients with VEGF therapy refractory RCC.

SECONDARY OBJECTIVES:

I. To assess overall response rate (ORR) and overall survival (OS). (Clinical) II. To assess time to treatment failure (TTF). (Clinical) III. To determine whether baseline AKT activation is predictive for clinical benefit after treatment with MK-2206 or everolimus. (Pre-clinical/exploratory) IV. To determine whether circulating cytokines and angiogenic factors predict for clinical benefit after treatment with MK-2206 or everolimus. (Pre-clinical/exploratory) V. To assess impact of karyotype on outcome in patients treated with MK-2206 or everolimus. (Pre-clinical/exploratory)

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

ARM I: Patients receive Akt inhibitor MK2206 orally (PO) on days 1, 8, 15, and 22. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Patients who are progression free after 1 year may receive a 12 week study drug supply of Akt inhibitor MK2206.

ARM II: Patients receive everolimus PO once daily (QD) on days 1-28. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months.

Arms: arm 1: Patients receive Akt inhibitor MK2206 PO on days 1, 8, 15, and 22. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. Patients who are progression free after 1 year may receive a 12 week study drug supply of Akt inhibitor MK2206. arm 2: Patients receive everolimus PO QD on days 1-28. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Akt Inhibitor MK2206 intervention 2: Everolimus intervention 3: Laboratory Biomarker Analysis
Intervention descriptions: intervention 1: Given PO intervention 2: Given PO intervention 3: Optional correlative studies

Protocol documents:
Prot_SAP_000.pdf: 
i 
SUMMARY OF CHANGES 
 
For Protocol Amendment # to:  A Randomized Phase 2 Study of MK-2206 in Comparison with 
Everolimus in Refractory Renal Cell Carcinoma 
 
NCI Protocol #:  8727 
Local Protocol #:  2010-0247 
 
NCI Version Date:  June 11, 2018 
Protocol Date:  June 11, 2018 
 
 
# 
Section 
Page(s) 
Change 
1 
Header 
All 
Rationale:  The header date is being updated 
 
Old Text:  November 8, 2016 
 
New Text : June 11, 2018  


ii 
2 
Comprehensive Adverse 
Events and Potential 
Risks list (CAEPR)  
for 
Everolimus (RAD-001, 
NSC 733504) 
 
42 
through 
45 
Rationale: The Comprehensive Adverse Events and Potential Risks list (CAEPR) for Everolimus 
(RAD-001, NSC 733504)  is being updated with the most recent version number (Version 2.3, June 30, 
20161). 
 
Old Text 
 
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. 
 
2Includes diarrhea, enteritis, enterocolitis, colitis, defecation urgency, and steatorrhea. 
 
3Includes stomatitis, aphthous stomatitis, gingival pain/swelling/ulceration, glossitis, glossodynia, lip 
ulceration, mouth ulceration, tongue ulceration, and mucosal inflammation. 
 
4Infection includes all 75 infection sites under the INFECTIONS AND INFESTATIONS SOC. 
 
5Everolimus delays wound healing and increases the occurrence of wound-related complications like 
wound dehiscence, wound infection, incisional hernia, lymphocele, and seroma. 
 
6Hyperglycemia may result in either exacerbation of or development new onset diabetes mellitus. 
 
7Includes pneumonitis, interstitial lung disease, lung infiltration, pulmonary alveolar hemorrhage, 
pulmonary toxicity, alveolitis, pulmonary fibrosis, and restrictive pulmonary disease. 
 
8Includes agitation, anxiety, panic attack, aggression, abnormal behavior, and obsessive compulsive 
disorder. 
 
9Patients taking concomitant ACE inhibitor therapy may be at increased risk for angioedema. 
 
Adverse events reported on Everolimus (RAD-001) trials, but for which there is insufficient evidence to 
suggest that there was a reasonable possibility that Everolimus (RAD-001) caused the adverse event: 
 
CARDIAC DISORDERS - Atrial fibrillation; Chest pain - cardiac; Heart failure; Myocardial infarction; 
Sinus tachycardia 
ENDOCRINE DISORDERS - Endocrine disorders - Other (increased blood follicle stimulating 
hormone [FSH] levels); Endocrine disorders - Other (increased blood luteinizing hormone [LH] levels) 
EYE DISORDERS - Blurred vision; Conjunctivitis 
GASTROINTESTINAL DISORDERS - Constipation; Dyspepsia; Dysphagia; Flatulence; 
Hemorrhoids; Oral pain; Periodontal disease 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Edema face; 
Irritability; Non-cardiac chest pain; Pain 
HEPATOBILIARY DISORDERS - Hepatic failure 
IMMUNE SYSTEM DISORDERS - Allergic reaction 
INVESTIGATIONS - Blood bilirubin increased; CPK increased; GGT increased; Investigations - Other 
(increased lactate dehydrogenase) 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hypercalcemia; Hyperkalemia; 
Hypernatremia; Hyponatremia; Metabolism and nutrition disorders - Other (hyperlipidemia) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Bone pain; Musculoskeletal 
and connective tissue disorder - Other (muscle spasms) 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - 
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other (ovarian cysts) 
NERVOUS SYSTEM DISORDERS - Paresthesia 
PSYCHIATRIC DISORDERS - Agitation; Anxiety8; Depression 
RENAL AND URINARY DISORDERS - Proteinuria; Urinary frequency 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Dysmenorrhea; Irregular menstruation; 
Menorrhagia; Vaginal hemorrhage 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Nasal congestion; 
Pharyngolaryngeal pain; Pleural effusion; Respiratory failure; Sore throat 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Nail loss; Palmar-plantar erythrodysesthesia 
syndrome; Skin and subcutaneous tissue disorders - Other (angioedema)9; Skin and subcutaneous tissue 
disorders - Other (skin lesion); Skin ulceration 
VASCULAR DISORDERS - Flushing; Hypertension; Lymphedema; Phlebitis; Thromboembolic event; 
Vascular disorders - Other (hemorrhage) 
 
Note: Everolimus (RAD-001) 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. 
 


iii 
New Text: 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of reported 
and/or potential adverse events (AE) associated with an agent using a uniform presentation of events by 
body system. In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to 
Expedited Reporting (SPEER), appears in a separate column and is identified with bold and italicized 
text. This subset of AEs (SPEER) is a list of events that are protocol specific exceptions to expedited 
reporting to NCI (except as noted below). Refer to the 'CTEP, NCI Guidelines: Adverse Event 
Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for further 
clarification. Frequency is provided based on 3033 patients. Below is the CAEPR for Everolimus 
(RAD-001). 
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 2.4, July10, 20171 
 
 Adverse Events with Possible  
 Relationship to Everolimus (RAD-001) 
 (CTCAE 4.0 Term) 
[n= 3033] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
Anemia 
 
 
 Anemia (Gr 2) 
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
  
 
Constipation 
 
  
Diarrhea2 
 
 
 Diarrhea2 (Gr 2) 
Mucositis oral3  
 
 Mucositis oral3 (Gr 2) 
 
Nausea 
 
 Nausea (Gr 2) 
 
Vomiting 
 
 Vomiting (Gr 2) 
GENERAL DISORDERS AND ADMINISTRATION SITE 
CONDITIONS 
  
 
Edema limbs 
 
 Edema limbs (Gr 2) 
Fatigue 
 
 
 Fatigue (Gr 2) 
 
Fever 
 
 Fever (Gr 2) 
INFECTIONS AND INFESTATIONS 
  
 
Infection4 
 
 Infection4 (Gr 2) 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS   
 
 
Wound complication5 
  
INVESTIGATIONS 
  
 
Alanine 
aminotransferase 
increased 
 
 Alanine aminotransferase 
increased (Gr 2) 
 
Alkaline phosphatase 
increased 
 
 Alkaline phosphatase 
increased (Gr 2) 
 
Aspartate 
aminotransferase 
increased 
 
 Aspartate 
aminotransferase 
increased (Gr 2) 
 
Cholesterol high 
 
 Cholesterol high (Gr 2) 
 
Creatinine increased 
 
 Creatinine increased (Gr 
2) 
 
Lymphocyte count 
decreased 
 
 Lymphocyte count 
decreased (Gr 2) 
 
Neutrophil count 
decreased 
 
 Neutrophil count 
decreased (Gr 2) 
 
Platelet count decreased  
 Platelet count decreased 
(Gr 2) 


iv 
 
Weight loss 
 
  
 
White blood cell 
decreased 
 
 White blood cell 
decreased  
(Gr 2) 
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
 Anorexia (Gr 2) 
 
Hyperglycemia6 
 
 Hyperglycemia6 (Gr 2) 
 
Hypertriglyceridemia 
 
 Hypertriglyceridemia (Gr 
2) 
 
Hypophosphatemia 
 
 Hypophosphatemia (Gr 2) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE 
DISORDERS 
  
 
Arthralgia 
 
  
 
Back pain 
 
  
 
Pain in extremity 
 
  
NERVOUS SYSTEM DISORDERS 
  
 
Dysgeusia 
 
  
 
Headache 
 
 Headache (Gr 2) 
RENAL AND URINARY DISORDERS 
  
 
 
Acute kidney injury 
  
RESPIRATORY, THORACIC AND MEDIASTINAL 
DISORDERS 
  
 
Cough 
 
 Cough (Gr 2) 
 
Dyspnea 
 
 Dyspnea (Gr 2) 
 
Epistaxis 
 
 Epistaxis (Gr 2) 
 
Pneumonitis7 
 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Dry skin 
 
  
 
Pruritus 
 
  
Rash maculo-
papular 
 
 
 Rash maculo-papular (Gr 
2) 
 
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. 
 
2Includes diarrhea, enteritis, enterocolitis, colitis, defecation urgency, and steatorrhea. 
 
3Includes stomatitis, aphthous stomatitis, gingival pain/swelling/ulceration, glossitis, glossodynia, lip 
ulceration, mouth ulceration, tongue ulceration, and mucosal inflammation. 
 
4Infection includes all 75 infection sites under the INFECTIONS AND INFESTATIONS SOC. 
 
5Everolimus delays wound healing and increases the occurrence of wound-related complications like 
wound dehiscence, wound infection, incisional hernia, lymphocele, and seroma. 
 
6Hyperglycemia may result in either exacerbation of or development new onset diabetes mellitus. 
 
7Includes pneumonitis, interstitial lung disease, lung infiltration, pulmonary alveolar hemorrhage, 
pulmonary toxicity, alveolitis, pulmonary fibrosis, and restrictive pulmonary disease. 
 
8Patients taking concomitant ACE inhibitor therapy may be at increased risk for angioedema. 
 
9Includes agitation, anxiety, panic attack, aggression, abnormal behavior, and obsessive 
compulsive disorder. 
 
 
Adverse events reported on Everolimus (RAD-001) trials, but for which there is insufficient evidence to 
suggest that there was a reasonable possibility that Everolimus (RAD-001) caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other 
(thrombotic microangiopathy) 


v 
# 
Section 
Page(s) 
Change 
CARDIAC DISORDERS - Atrial fibrillation; Cardiac disorders - Other (myocardial abnormality); 
Chest pain - cardiac; Heart failure; Left ventricular systolic dysfunction; Myocardial infarction; Sinus 
bradycardia; Sinus tachycardia; Supraventricular tachycardia 
ENDOCRINE DISORDERS - Endocrine disorders - Other (increased blood follicle stimulating 
hormone [FSH] levels); Endocrine disorders - Other (increased blood luteinizing hormone [LH] levels); 
Endocrine disorders - Other (low testosterone); Hypothyroidism 
EYE DISORDERS - Blurred vision; Conjunctivitis; Keratitis 
GASTROINTESTINAL DISORDERS - Ascites; Colitis; Dry mouth; Dyspepsia; Dysphagia; 
Flatulence; Gastroesophageal reflux disease; Gastrointestinal disorders - Other (Dieulafoy's lesion); 
Hemorrhoids; Intra-abdominal hemorrhage; Oral pain; Pancreatitis; Periodontal disease; Toothache 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Edema face; 
Edema trunk; Flu like symptoms; Irritability; Non-cardiac chest pain; Pain 
HEPATOBILIARY DISORDERS - Hepatic failure; Hepatobiliary disorders - Other (hepatomegaly) 
IMMUNE SYSTEM DISORDERS - Allergic reaction 
INVESTIGATIONS - Activated partial thromboplastin time prolonged; Blood bilirubin increased; CPK 
increased; GGT increased; INR increased; Investigations - Other (bicarbonate decreased); Investigations 
- Other (increased lactate dehydrogenase); Investigations - Other (low density lipoprotein raised); 
Investigations - Other (thrombocythemia) 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Glucose intolerance; Hypercalcemia; 
Hyperkalemia; Hypoalbuminemia; Hypocalcemia; Hypokalemia; Hypomagnesemia; Hyponatremia; 
Metabolism and nutrition disorders - Other (high ammonia); Metabolism and nutrition disorders - Other 
(hyperlipidemia) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Bone pain; Chest wall pain; 
Generalized muscle weakness; Muscle weakness lower limb; Musculoskeletal and connective tissue 
disorder - Other (muscle spasms); Myalgia 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - 
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other (ovarian cysts) 
NERVOUS SYSTEM DISORDERS - Dizziness; Encephalopathy; Hydrocephalus; Lethargy; 
Paresthesia 
PSYCHIATRIC DISORDERS - Agitation; Anxiety8; Delirium; Depression; Insomnia; Mania 
RENAL AND URINARY DISORDERS - Hematuria; Proteinuria; Urinary frequency 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Dysmenorrhea; Genital edema; Irregular 
menstruation; Menorrhagia; Vaginal hemorrhage 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Bronchopulmonary hemorrhage; 
Pharyngolaryngeal pain; Pleural effusion; Respiratory failure; Respiratory, thoracic and mediastinal 
disorders - Other (rales); Respiratory, thoracic and mediastinal disorders - Other (rhinorrhea); Sore 
throat; Voice alteration 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Nail loss; Palmar-plantar erythrodysesthesia 
syndrome; Rash acneiform; Skin and subcutaneous tissue disorders - Other (angioedema)9; Skin and 
subcutaneous tissue disorders - Other (nail disorder); Skin and subcutaneous tissue disorders - Other 
(skin lesion); Skin ulceration 
VASCULAR DISORDERS - Flushing; Hypertension; Lymphedema; Phlebitis; Thromboembolic event; 
Vascular disorders - Other (acute bowel ischemia); Vascular disorders - Other (hemorrhage) 
 
 
Note: Everolimus (RAD-001) 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. 
 
 
 


vi 
# 
Section 
Page(s) 
Change 
3 
7.2 Adverse Event 
Characteristics  
45 
Rationale: Current ongoing protocol transitioning from CTCAE v4.0 to v5.0 with v5.0 start date only. 
 
Old Text: 
CTCAE term (AE description) and grade: CTCAE term (AE description) and grade: NCI Common 
Terminology Criteria for Adverse Events (CTCAE) v.4 will be utilized for AE reporting. The CTCAE 
is identified and located on the CTEP website at http://ctep.cancer.gov/protocolDevelopment/electronic 
applications/ctc.htm. All appropriate treatment areas should have access to a copy of CTCAE v4. 
 
New Text: 
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 version 
utilized until March 31, 2018 for AE reporting. CTCAE version 5.0 will be utilized for AE 
reporting beginning April 1, 2018. All appropriate treatment areas should have access to a copy of 
the CTCAE version 5.0. A copy of the CTCAE version 5.0 can be downloaded from the CTEP 
web site 
http://ctep.cancer.gov/protocolDevelopment /electronic applications/ctc.htm. 
 
4 
7.3 Expedited Adverse 
Event Reporting  
46 
Rationale: Section 7.3.3 Phase 2 and 3 Trials Reporting Guidelines – CTEP-AERS  
Progressive disease Example from CTEP Generic Protocol Template 
 
Old Text: 
Note: All death on study requires both routine and expedited reporting, regardless of causality. 
Attribution to treatment or other cause must be provided.  
 
New Text: 
Note: A death on study requires both routine and expedited reporting, regardless of causality. 
Attribution to treatment or other cause must be provided.  
 
Death due to progressive disease should be reported as Grade 5 “Disease progression” in the system 
organ class (SOC) “General disorders and administration site conditions.” Evidence that the death was a 
manifestation of underlying disease (e.g., radiological changes suggesting tumor growth or progression: 
clinical deterioration associated with a disease process) should be submitted.  
 
Pregnancy loss Example: 
 
Pregnancy loss 
• 
Pregnancy loss is defined in CTCAE as “Death in utero 
• 
Any pregnancy loss should be reported expeditiously, as Grade 4 
“Pregnancy loss” under the Pregnancy, puerperium and perinatal conditions 
SOC. 
• 
A pregnancy loss should NOT be reported as a Grade 5 event under 
• 
the Pregnancy, puerperium and perinatal conditions SOC, as currently 
CTEPAERS 
• 
recognizes this event as a patient death. 
 
Death neonatal Example: 
A neonatal death should be reported expeditiously as Grade 4, “Death neonatal” under the General 
disorders and administration SOC. 
 
 
 
 
 


NCI Protocol #:  8727 
Version Date:   June 11, 2018 
 
1 
NCI Protocol #: 
8727 
 
Local Protocol #: 
2010-0247 
 
TITLE:  A Randomized Phase 2 Study of MK-2206 in Comparison with Everolimus in 
Refractory Renal Cell Carcinoma 
 
Coordinating Center: 
 
 
The University of Texas M. D. Anderson Cancer Center 
 
*Principal Investigator: 
Eric Jonasch, M.D.  
Department of GU Medical Oncology 
1155 Pressler Street, Unit 1374 
Houston TX 77030 
713-792-2830 
713-745-1625 
ejonasch@mdanderson.org 
 
 
Co-Investigators: 
 
 
 
Amado Zurita, M.D. 
1155 Pressler Street, Unit 1374 
Houston TX 77030 
713-792-2830 
713-745-1625 
azurita@mdanderson.org 
 
 
Ana Aparicio, M.D. 
1155 Pressler Street, Unit 1374 
Houston TX 77030 
713-792-2830 
713-745-1625 
aaparicio@mdanderson.org 
 
John Araujo, M.D., Ph.D. 
1155 Pressler Street, Unit 1374 
Houston TX 77030 
713-792-2830 
713-745-1625 
johna@mdanderson.org 
 
Padmanee Sharma, M.D., Ph.D. 
1155 Pressler Street, Unit 1374 
Houston TX 77030 
713-792-2830 
713-745-1625 
 
padsharma@mdanderson.org 
 


NCI Protocol #:  8727 
Version Date:   June 11, 2018 
 
2 
Paul Corn, M.D., Ph.D. 
1155 Pressler Street, Unit 1374 
Houston TX 77030 
713-792-2830 
713-745-1625 
pcorn@mdanderson.org 
 
Shi-Ming Tu, M.D., Ph.D. 
1155 Pressler Street, Unit 1374 
Houston TX 77030 
713-792-2830 
713-745-1625 
stu@mdanderson.org 
 
Nizar Tannir, M.D. 
1155 Pressler Street, Unit 1374 
Houston TX 77030 
713-792-2830 
713-745-1625 
ntannir@mdanderson.org 
 
Pheroze Tamboli, M.D. *Associate Investigator is NOT 
responsible for patient care and therefore does not require a 
current registration packet.* 
1515 Pressler Street, Unit 0085 
Houston TX 77030 
713-794-5445 
713-745-3740 
ptamboli@mdanderson.org 
 
Przemyslaw Twardowski MD 
City of Hope (COH PI) 
1500 E. Duarte Rd 
Duarte, CA 91010 
626-256-HOPE (4673) x 62307 
626-301-8233 
ptwardowski@coh.org 
 
David I. Quinn MD PhD FRACP 
University of Southern California (USC PI) 
1441 Eastlake Ave #3453 
Los Angeles CA 90033 
323-865-3956 /323-865-3000 
323-865-0061 
diquinn@usc.edu 
 


NCI Protocol #:  8727 
Version Date:   June 11, 2018 
 
3 
Primo N. Lara, Jr., MD 
UC Davis Cancer Center (UCD PI) 
4501 X Street 
Sacramento, CA  95817 
916-734-3772 
916-734-7946 
primo.lara@ucdmc.ucdavis.edu 
 
Leonard J. Appleman, MD, PhD 
University of Pittsburgh Cancer Institute (UOP PI) 
UPMC Cancer Pavilion, 5th Floor 
5150 Center Avenue 
Pittsburgh, PA 15232 
412-648-6507 
412-648-6579 
applemanlj@upmc.edu 
 
Joseph J. Drabick MD FACP 
Penn State Milton S. Hershey Medical Center (PSU PI) 
500 University Drive CH46 
Hershey, PA  17033-0850 
717-531-8678 
717-531-5076 
jdrabick@psu.edu 
 
Mark McNamara, MD  
City of Hope Medical Group, Inc., (COHMG) 
50 Bellefontaine Street 
Pasadena, CA 91105 
626-396-2900 
626-396-2911 
mmcnamara@coh.org 
 
Solomon Hamburg, MD 
Tower Cancer Research Foundation (TOW) 
9090 Wilshire Blvd., 2nd Floor 
Beverly Hills, CA  90211 
310-285-7427 
310-285-7298 
hamburghs@toweroncology.com 
 
 
 
 
 
 


NCI Protocol #:  8727 
Version Date:   June 11, 2018 
 
4 
NCI Supplied Agent(s):  MK-2206 (NSC 749607; IND # 109493) 
 
IND Sponsor:  NCI 
 
Protocol Type / Version # / Version Date:  Revision/ Local Version June 11, 2018  
 
 


NCI Protocol #:  8727 
Version Date:   June 11, 2018 
 
5 
SCHEMA 
 
 

Biopsy proven RCC 

Failed at least one anti 
VEGF therapy 

PS 0-1 

Prior nephrectomy 
Arm B 
Everolimus 
10mg PO Daily 
Arm A 
MK-2206 
200mg PO once weekly  
2:1 Randomization 


NCI Protocol #:  8727 
Version Date:   June 11, 2018 
 
6 
TABLE OF CONTENTS 
 
SUMMARY OF CHANGES ........................................................................................................... i 
SCHEMA .........................................................................................................................................5 
1. 
OBJECTIVES ......................................................................................................................8 
1.1 
Primary Objectives ...................................................................................................8 
1.2 
Secondary Objectives ...............................................................................................8 
2. 
BACKGROUND .................................................................................................................8 
2.1 
Study Disease ...........................................................................................................8 
2.2 
CTEP Supplied Investigational Agent(s) .................................................................9 
2.3 
Other Agent(s) .......................................................................................................17 
2.4 
Rationale ................................................................................................................24 
2.5 
Correlative Studies Background ............................................................................25 
3. 
PATIENT SELECTION ....................................................................................................26 
3.1 
Eligibility Criteria ..................................................................................................26 
3.2 
Exclusion Criteria ..................................................................................................27 
3.3 
Inclusion of Women and Minorities ......................................................................28 
4. 
REGISTRATION PROCEDURES ...................................................................................29 
4.1 
General Guidelines .................................................................................................29 
4.2 
Registration Process ...............................................................................................29 
5. 
TREATMENT PLAN ........................................................................................................30 
5.1 
Agent Administration .............................................................................................30 
5.2 
Screening and Evaluation On-Study ......................................................................31 
5.3 
General Concomitant Medication and Supportive Care Guidelines ......................33 
5.4 
Definition of Dose-Limiting Toxicity ....................................................................33 
5.5 
Duration of Therapy ...............................................................................................34 
5.6 
Duration of Follow Up ...........................................................................................34 
5.7 
Criteria for Removal from Study ...........................................................................35 
6. 
DOSING DELAYS/DOSE MODIFICATIONS................................................................35 
6.1 
MK-2206 ................................................................................................................35 
6.2 
Everolimus .............................................................................................................36 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................39 
7.1 
Comprehensive Adverse Events and Potential Risks Lists (CAEPRs) .................40 
7.2 
Adverse Event Characteristics ...............................................................................45 
7.3 
Expedited Adverse Event Reporting ......................................................................46 
7.4 
Routine Adverse Event Reporting .........................................................................48 
7.5 
Secondary AML/MDS ...........................................................................................48 


NCI Protocol #:  8727 
Version Date:   June 11, 2018 
 
7 
8. 
PHARMACEUTICAL INFORMATION ..........................................................................48 
8.1 
CTEP-Supplied Investigational Agents .................................................................48 
8.2 
Commercial Agent: Everolimus ............................................................................50 
9. 
CORRELATIVE/SPECIAL STUDIES .............................................................................50 
10. 
STUDY CALENDAR .......................................................................................................51 
11. 
MEASUREMENT OF EFFECT........................................................................................52 
11.1 
Antitumor Effect – Solid Tumors ..........................................................................52 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS ...........................................61 
12.1 
Data Reporting .......................................................................................................61 
12.2 
CTEP Multicenter Guidelines ................................................................................62 
12.3 
Collaborative Agreements Language .....................................................................62 
13. 
STATISTICAL CONSIDERATIONS...............................................................................64 
13.1 
Study Design/Endpoints.........................................................................................64 
13.2 
Sample Size/ Power Calculation ............................................................................65 
13.3 
Stratification Factors ..............................................................................................65 
13.4 
Statistical Analysis Plan .........................................................................................65 
13.5 
Reporting and Exclusions ......................................................................................66 
REFERENCES ..............................................................................................................................67 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ..................................................70 
APPENDIX B 
CTEP MULTICENTER GUIDELINES ....................................................71 
APPENDIX C 
LIST OF CYP3A4 INHIBITORS AND INDUCERS ...............................73 
APPENDIX D 
MEDICATIONS THAT MAY CAUSE QTc PROLONGATION ...........74 
APPENDIX E 
PATIENT’S MEDICATION DIARY .......................................................76 
APPENDIX F 
PATIENT’S MEDICATION DIARY .......................................................77 
APPENDIX G 
SNP Analysis .............................................................................................79 
APPENDIX H 
Tissue Microarray (TMA) ..........................................................................82 
APPENDIX I 
Cytokine and Angiogenesis Factor Analysis:  Amado Zurita, Collaborator
 
84 
APPENDIX J 
MSKCC Risk Stratification .......................................................................88 
APPENDIX K 
Multi-Center Study Management Plan ......................................................89 


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1. OBJECTIVES 
 
1.1 
Primary Objectives 
 
1.1.1 To assess progression free survival (PFS) of vascular endothelial growth factor 
(VEGF) therapy refractory renal cell carcinoma (RCC) patients who receive either 
MK-2206 or everolimus. 
1. To assess safety of MK-2206 in patients with VEGF therapy refractory RCC 
 
1.2 
Secondary Objectives 
 
Clinical:  
1.  
To assess overall response rate (ORR) and overall survival (OS) 
2.  
To assess time to treatment failure (TTF) 
 
Pre-clinical/Exploratory:  
1.  
To determine whether baseline AKT activation is predictive for clinical benefit after 
treatment with MK-2206 or everolimus.   
2.  
To determine whether circulating cytokines and angiogenic factors predict for clinical 
benefit after treatment with MK-2206 or everolimus.  
3.  
To assess impact of karyotype on outcome in patients treated with MK-2206 or 
everolimus.  
 
2. BACKGROUND 
 
2.1 
Study Disease 
Renal cell carcinoma (RCC) comprises more than 90 percent of all kidney cancer cases 
and accounts for approximately 3 percent of all adult malignancies.  It affected more than 
40,000 individuals in the USA in 2009, and was directly responsible for approximately 
13,000 deaths.  Nearly one third of patients with RCC present with metastases at the time 
of diagnosis, and up to 50 percent develop recurrence after nephrectomy for localized 
disease.  Surgical removal of the primary lesion is the only clearly effective therapy in the 
non-metastatic setting.  No adjuvant therapy has been shown to be effective in patients 
with RCC post-nephrectomy in the non-metastatic setting.   
 
If metastases develop, cure is difficult, and most patients ultimately succumb to their 
disease.  Commonly available clinical and laboratory parameters can be used to stratify 
patients into different risk groups.  Investigators at Memorial Sloan Kettering Cancer 
Center (MSKCC) demonstrated that patients who went on to receive immunotherapy 
could be categorized into three discrete risk categories, using five variables: Karnofsky 
performance status of less than 80; time from diagnosis to treatment of less than one year; 
lactate dehydrogenase levels one and a half times the upper limit of normal, anemia, and 
hypercalcemia.  A recent analysis in patients who received anti-VEGF inhibitors came up 
with a similar list.  Unfortunately the mechanism underpinning these risk factors is poorly 
understood, and they cannot easily be used as predictive biomarkers.  


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9 
 
A number of different approaches are taken to control metastatic RCC.  In patients with 
oligometastatic disease, metastasectomy is associated with long term disease free 
survival.  Systemic therapy options include immunotherapy, with modest overall survival 
(OS) increases seen in patients treated with interferon alpha , and a small but consistent 
rate of complete responses (CR) seen in patients treated with high-dose interleukin 2 (IL-
2).  As the molecular biology of RCC was elucidated, it became apparent that clear cell 
RCC (CCRCC) was frequently associated with mutations in the von Hippel Lindau 
(VHL) gene.  Mutated VHL resulted in unbridled hypoxia inducible factor (HIF) driven 
transcription of various proangiogenic factors, including VEGF, transforming growth 
factor alpha, platelet derived growth factor, GLUT1, and carbonic anhydrase nine.  
Inhibitors of inappropriate angiogenesis were developed and tested, including sorafenib 
(Nexavar, Bayer AG), sunitinib (Sutent, Pfizer Corp), bevacizumab (Avastin, Roche 
AG), and pazopanib (Votrient, Glaxo Smith Kline PLC).  Each of these agents was Food 
and Drug Administration (FDA) approved for advanced RCC between 2005 and 2009.  
Most patients on these studies were diagnosed with CCRCC, had good or intermediate 
MSKCC risk criteria, and had prior nephrectomy.   
 
At the same time, clinical experience with the mammalian target of rapamycin (mTOR) 
inhibitor sirolimus ester temsirolimus (Torisel, Pfizer Corp) suggested a clinical signal in 
patients with cytokine refractory RCC.  Subset analysis suggested that patients with poor 
risk features may have derived differential benefit from this agent.  A phase III study was 
performed recruiting patients with three or more of six risk factors, which included the 
five MSKCC risk criteria and the presence of at least two organ sites of disease. The 
patient population also differed in that only two thirds had undergone prior nephrectomy, 
and only 80 percent had clear cell histology.   The OS of temsirolimus treated patients 
was significantly longer than in the IFN treated population, and a combination 
temsirolimus-IFN arm ended up with outcomes somewhere in between the monotherapy 
arms.  Everolimus (Afinitor, Novartis AG), an orally administered sirolimus ester, was 
tested against placebo in patients who had failed either sorafenib or sunitinib, and showed 
a 4.0 month PFS versus 1.9 months in the placebo arm.  Both agents are FDA approved, 
with temsirolimus approved for advanced RCC, and everolimus approved in sorafenib 
and sunitinib refractory patients.   
 
2.2 
CTEP Supplied Investigational Agent(s) 
 
MK-2206 
 
The PI3K/AKT pathway is downstream of the common growth factor tyrosine kinase 
receptors (TKR), including EGFR, HER2, IGFR, etc., and is a likely driver of tumor 
progression in most carcinomas (Altomare and Testa, 2005; Hennessy et al., 2005; 
Steelman et al., 2008). AKT protein kinase is activated in a substantial proportion of 
human solid tumors (breast, endometrial, ovarian, prostate, pancreatic, colon, gastric, and 
non-small cell lung cancer [NSCLC]).  Upregulation of AKT can be caused by direct 
amplification/mutation of AKT, or by overexpression of TKRs, PI3K and RAS, and/or by 
inactivation of the tumor suppressor PTEN.  Because of its key function in cell survival, 


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10 
AKT plays a pivotal role in rendering tumor cells insensitive or resistant to chemotherapy 
or targeted agents.   
 
The rationale for the use of an AKT inhibitor in treatment of various malignancies is 
included in the following references (Staal, 1987; Shayesteh et al., 1999; Fry, 2001; 
Tanno et al., 2001; Testa and Bellacosa, 2001; Hu et al., 2002; Rahman et al., 2002; Min 
et al., 2003; Lee et al., 2004; St-Germain et al., 2004; Altomare and Testa, 2005; 
Hennessy et al., 2005; Kirkegaard et al., 2005; Nakanishi et al., 2005; Oki et al., 2005; 
Saal et al., 2005; Shoman et al., 2005; Vestey et al., 2005; Wolf and Slomovitz, 2005; 
Konecny et al., 2006; Kornblau et al., 2006; Nakayama et al., 2006; Oza, 2006; Uddin et 
al., 2006; Sosman et al., 2007; Cejka et al., 2008; Engelman et al., 2008; Han et al., 
2008; Kinkade et al., 2008; Steelman et al., 2008; Kawauchi et al., 2009; Salvesen et al., 
2009).   
 
MK-2206 is the first allosteric inhibitor of AKT to enter clinical development 
(Investigator's Brochure, 2009).  MK-2206 demonstrated AKT inhibition and 
antiproliferative activity as single agent and in combination with other agents in multiple 
human cancer cell lines, such as breast, ovarian, lung, and prostate.  MK-2206 synergized 
antitumor effects of docetaxel, erlotinib, and carboplatin in vivo in various human tumor 
xenograft models. 
 
Mechanism of Action 
 
MK-2206 is a selective allosteric inhibitor of AKT (Investigator's Brochure, 2009).  MK-
2206 does not bind to the active site of AKT, and consequently does not compete with 
either ATP or peptide substrate for binding to AKT.  It is equally potent against the two 
human AKT isoforms, AKT1 and AKT2, and ~5-fold less potent against AKT3.   
 
Nonclinical Studies 
 
In Vitro Activity Studies  
 
In vitro single-agent activity of MK-2206 
 
In an in vitro kinase assay with GSK3 alpha peptide as substrate, MK-2206 strongly 
inhibited kinase activity of the three human isoforms of AKT, AKT1, 2, and 3, with 50% 
inhibitory concentration (IC50) values of 8, 12, and 65 nM, respectively.  MK-2206 
exhibited no inhibition (IC50>50 micromol/L (mcM) against the (pleckstrin-homology 
domain) deletion mutants of AKT, indicating that this domain is essential for binding 
MK-2206 to AKT.  Apart from AKT, MK-2206 was tested at a single concentration of 1 
mcM against a panel of ~250 kinases without demonstrating significant (≥50%) 
inhibition against any kinase. 
 
The antiproliferative potency of MK-2206 was evaluated against a panel of tumor cell 
lines using in vitro proliferation and viability assays.  Among 52 cell lines, 18 cell lines 
were highly sensitive (IC50<1 mcM), 7 were moderately sensitive (IC50=1-5 mcM), and 


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11 
27 cell lines were insensitive (IC50>5 mcM) to MK-2206.  Highly sensitive cell lines 
included breast, ovarian, prostate, non-small cell lung cancer (NSCLC), small cell lung 
cancer (SCLC), gastric, and endometrial cancer.  At least one of the following genetic 
defects was represented in the majority of sensitive cell lines:  PTEN mutation, PI3KCA 
mutation, AKT amplification, or genomic amplification of HER2 or MET.  Nine of 27 cell 
lines that were insensitive to MK-2206 had either PTEN or PI3KCA mutation, or were 
deficient in PTEN protein.  Among eight cell lines carrying RAS or BRAF activating 
mutation, six were insensitive to MK-2206.  
 
MK-2206 activity in combination with other agents 
 
In a proliferation/viability assay, various degrees of synergism between MK-2206 and 
lapatinib (a dual EGFR/HER2 inhibitor) were observed in eight breast cancer cell lines.   
MK-2206 and docetaxel demonstrated additive to synergistic antiproliferative activity 
against nine breast-cancer cell lines, however, the effects were dependent on agent 
sequence.  Enhancement of antitumor activity occurred only when cells were treated first 
with docetaxel and then exposed to MK-2206.  In contrast, co-administration of the two 
agents resulted in antagonism.  Combination of MK-2206 with erlotinib produced various 
degrees of synergism in nine NSCLC cell lines, including A431 epidermoid cells 
overexpressing EGFR. 
 
MK-2206 synergized antitumor activity of carboplatin, gemcitabine, doxorubicin, 
camptothecin, or 5-FU in ovarian, prostate and NSCLC cell lines.  Antitumor activity of 
MK-2206/carboplatin, demonstrated in the ovarian cell line A2780, was accompanied 
with enhanced apoptosis (cleavage of caspases 3 and 7).  However, the effect was 
dependent on the sequence of agent administration, as it occurred only when cells were 
exposed to carboplatin before or simultaneously with MK-2206.  Enhancement of 
apoptosis did not occur when MK-2206 preceded carboplatin.  
 
In Vivo Activity Studies 
 
MK-2206 monotherapy administered as a single dose (10-240 mg/kg) to mice bearing 
human ovarian tumor (A2780) potently inhibited phosphorylation of AKT1/2 in blood as 
well as in tumor tissue.  After a single dose of 30, 120, or 240 mg/kg of MK-2206, ≥80% 
inhibition of AKT1/2 was achieved in peripheral blood; inhibition persisted at this level 
for 6 and 24 hours at the 120- and 240-mg/kg dose, respectively.  Pronounced inhibition 
(70-90%) of phosphorylation of AKT1/2 (pAKT1/2), lasting for at least 24 hours, was 
detected also in tumor tissue following the single 120- or 240- mg/kg dose.  MK-2206 
combinations with docetaxel, carboplatin, or erlotinib exhibited significantly more potent 
antitumor activity than each agent in monotherapy settings.  For example, a combination 
of MK-2206 and docetaxel, administered for 4 weeks as one weekly intravenous (IV) 
dose of docetaxel (30 mg/kg) followed 24 hours later by MK-2206 (240 or 480 mg/kg) 
given orally (PO) once a week (QW), produced strong antitumor responses in the A2780 
ovarian-cancer xenograft mouse model.  MK-2206 monotherapy was ineffective at all 
doses.  Although the combination was significantly more effective than docetaxel 
monotherapy, responses did not endure beyond the treatment period.  Tumor regression 


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12 
was also observed in PC-3 prostate xenograft model following sequential treatment with 
docetaxel and MK-2206 (24 hours later).  MK-2206 (120 mg/kg) was given three times 
per week (days 1, 3, 5) and docetaxel (5 mg/kg) once weekly on day 0.  Inhibition of 
tumor growth was also enhanced when MK-2206 was combined with carboplatin and 
erlotinib in the NSCLC H460 and H292 xenograft models, respectively.  Overall, the 
agents’ combinations were well-tolerated at the effective dose levels, although transient 
10-20%-weight loss was observed in some animals. 
 
Pharmacokinetics  
 
Pharmacokinetic (PK) parameters of MK-2206 in the rat, dog, and monkey are 
summarized in Table 1.  Across the species, MK-2206 showed moderate plasma 
clearance (Cl) and high volume of distribution at steady state (Vdss) and elimination half-
life (t1/2) ranging from 4 hours in rats to >12 hours in dogs and monkeys. 
 
Table 1.  Summary of nonclinical pharmacokinetics for MK-2206 
 
IV Route 
PO Route 
Species  
Dose 
(mpk)  
Cl 
(mL/min/kg)  
Vdss 
(L/kg)  
t1/2 
(h)  
Dose 
(mpk)  
AUC  
(mcM∙h)  
Cmax 
(mcM)  
tmax 
(h)  
F  
(%)  
Rat  
2 
27.6  
9  
4.2  
10  
2.1  
0.29  
5  
20  
 
 
 
 
 
100 
35.2 
2.76 
2.7 
35 
Dog  
0.5 
7.7  
8  
12.5  
2  
8.89  
0.38  
4  
83  
Rhesus  
0.5 
10.8  
11  
14  
 
Cl: clearance; Vdss: volume of distribution at steady state;  t1/2: elimination half-life; AUC: the area under 
the time-concentration curve; Cmax:  maximum drug concentration in plasma; tmax: time needed to 
achieve Cmax; F: oral availability; mcM: micromol/L; mpk: mg per kg; 
Vehicle: intravenous (IV): DMSO, oral route (PO): 0.5% methylcellulose (10 mpk), 30% Captisol (100 
mpk), or 1% methylcellulose (3 mpk)  
 
MK-2206 was significantly bound to plasma proteins (ranged from 96% to 88% in 
mice>rats>dogs>monkeys>humans) with moderate Cl in rats, but relatively low Cl in 
dogs and monkeys.   
 
The oral availability of MK-2206 was acceptable in rats (20%-35%) and better in dogs 
(83%).  Plasma Cl in rats occurred primarily by direct glucuronidation with <3% of MK-
2206 excreted in feces.  In dogs, elimination occurred via multiple metabolic pathways 
including oxidation followed by glucuronidation, direct glucuronidation, and formation 
of a carbamoyl glucuronide.  Relative to rats, a higher fraction (30%) of parent compound 
MK-2206 was excreted (urine, bile, and feces) in dogs.  Significant intestinal secretion 
was observed in dogs.  No metabolites of MK-2206 with biologic activity were noted.   
 
MK-2206 was also metabolized by oxidation in human liver microsomes, primarily via 
the 3A4 isoenzyme of the P450 cytochrome (CYP) enzyme complex.  MK-2206 was 
neither a potent inhibitor nor inducer of human CYPs, although at clinically relevant 
concentrations, it appeared to slightly induce CYP3A4.  Transport experiments in the P-


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13 
glycoprotein (P-gp)-transfected cell lines (L-MDR1) suggested that MK-2206 could be a 
P-gp substrate.  In addition, MK-2206 demonstrated weak inhibition of vectorial 
transport of digoxin in L-MDR1 cells (IC50 of 13.4 mcM).  
 
Toxicology 
 
In the 10-day tolerability studies, dose-limiting toxicities (DLTs) were observed at the 
dose of ≥200 mg/kg/day and ≥15 mg/kg/day in rats and dogs, respectively.  In a 4-week 
safety study in dogs, MK-2206 was administered at 2.5, 5, or 10 mg/kg PO every-other-
day (QOD) followed by a 2-week recovery period.  The 10-mg/kg dose was poorly 
tolerated as manifested by severe body-weight loss and other physical and 
histomorphological signs of toxicity, which required cessation of dosing by the end of the 
second week of treatment.  The 5-mg/kg dose was tolerated and although treatment-
related toxicities occurred, they were transient.  As no significant toxicities were 
observed in dogs at the 2.5-mg/kg dose, this dose was defined as NOAEL (no observed 
adverse effect level).  Exposure at this level characterized by the maximum plasma 
concentration (Cmax) and the area under the time-concentration curve (AUC0-48h) 
corresponded to 0.37 mcM and 8.52 mcM∙h, respectively.  A potential safety concern 
associated with MK-2206 therapy is prolongation of the QT-corrected (QTc) interval, 
which seemed to be dose-dependent.  While QTc-prolongation was persistent in dogs at 
the 10-mg/kg dose, it declined and returned to baseline between 24 to 72 hours post-
dosing at 5 and 2.5 mg/kg.  No cardiovascular changes were observed at the 1-mg/kg 
dose of MK-2206 (Cmax of 0.092 mcM and AUC0-24h of 1.6 mcM) within 48 hours 
following dosing in dogs.   
 
A tissue distribution study demonstrated that [14C] MK-2206 was widely distributed in 
Sprague Dawley (albino) and Long Evans (pigmented) rats except for the central nervous 
system.  The majority of the radioactivity went into the muscle, liver and skin shortly 
after dosing.  In Sprague Dawley and Long Evans rats, the radioactivity in most tissues 
was comparable.  It declined in parallel to that in blood and became negligible 3 days 
post-dose.  However, the radioactivity was more sustained at higher levels in the skin and 
the uveal tract of the eye in Long Evans than in Sprague Dawley rats.  The concentration 
(ng equivalent [14C]MK-2206/g tissue) in the skin and the uveal tract of Long Evans rats 
was 37- and 84-fold higher than that in the respective tissues of Sprague Dawley rats 24 
hours post-dose. 
 
An additional safety concern involves MK-2206-induced hyperglycemia and 
hyperinsulinemia.  MK-2206 induced hyperglycemia in all preclinical species tested.  In 
the most sensitive species, the dog, the glucose level was elevated by 24%-35%, when 
MK-2206 was administered at 5 mg/kg QOD for 4 weeks (AUC0-48 of 19.6 mcM∙h and 
Cmax of 0.73 mcM).  Such exposure is expected to correspond with human exposures 
achievable at the upper MK-2206 dosing range. 
 
Results from genetic toxicology assays demonstrated that MK-2206 was neither 
genotoxic nor mutagenic.   
 


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14 
Clinical Development of MK-2206   
 
Preliminary clinical PK/pharmacodynamic and safety experience is derived from a 
Merck-sponsored phase 1 study in healthy volunteers (HVs) and company phase 1 studies 
in patients with advanced solid tumors.   
 
Projections derived from preclinical PK and metabolism studies in dogs suggested that 
the target exposure corresponding to a plasma concentration of ≥100 nM MK-2206 over 
8 hours and AUC0-48h of ~2 mcM∙h in humans could be attained by MK-2206 dosed at 
30-70 mg QOD on a 28-day cycle schedule.  Clinical PK/pharmacodynamic data 
confirmed that the MK-2206 dose of 60 mg QOD conferred substantial and lasting 
inhibition of AKT as measured in tumor biopsies from cancer patients.  The 60-mg QOD 
dose level is being currently investigated as the maximum tolerated dose (MTD) in the 
expanded cohort of patients. 
 
Based on preclinical and clinical experience from Merck-sponsored studies, PK modeling 
and simulation analysis suggests potential benefit of a less frequent dosing schedule (i.e., 
QW).  It is potentially feasible to administer MK-2206 at higher dose levels on a less 
frequent dosing schedule to maximize significant or peak target inhibition.  This 
approach may also alleviate DLTs (e.g., skin rash) associated with accumulated exposure 
to MK-2206.  Dose escalation on a QW schedule is currently being evaluated at the MK-
2206 doses ranging from 90-300 mg. 
 
Clinical Pharmacokinetics 
 
The clinical PK for MK-2206 was evaluated in HVs receiving a single dose (0.25-100 
mg) and in cancer patients given a 30-, 45-, 60-, 75-, or 90-mg dose on the QOD schedule 
or 90-, 135-, 200-, 250-, or 300-mg dose on the QW schedule.   
 
Although Day 1 AUC0-48h and Cmax values achieved at ≤ 90 mg in cancer patients 
overlapped with the ranges observed in HVs, overall, MK-2206 exposures in cancer 
patients trended on average somewhat higher than those observed in HVs.  In all cohorts 
evaluated at ≤ 200 mg QW, exposures after the first and last dose in Cycle 1 were below 
the dog NOAEL AUC0-48h and Cmax values of 8.52 mcM•h and 365 nM, respectively.  
The mean first dose MK-2206 AUC0-48h and Cmax were 1.77 M•h and 62.2 nM, 
respectively, for 60 mg QOD, and 14.8 M•h and 466 nM, respectively, for 300 mg QW.  
The dog NOAEL exposures were exceeded in humans following the first dose of 300 mg 
QW.   
 
The variability in AUC0-48h and Cmax following the first dose, where it could be assessed, 
was low to moderate across all dose levels, with the coefficient of variation (CV) values 
ranging from approximately 10%–60%.  There does not appear to be a substantial or 
consistent departure from dose proportionality for either AUC0-48hr or Cmax following the 
first dose up to the 300-mg dose level, except for an apparent plateau in exposures 
observed at 200 mg (n=3).  Dose proportionality could not be reliably assessed beyond 
135 mg (n=4) due to limited numbers of patients at each dose level.   


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15 
 
Tmax and apparent terminal t1/2 values from cancer patients were generally within the 
ranges observed in HVs.  Median Tmax values ranged from 4–10 hours across all dose 
regimens and harmonic mean apparent terminal half-life (t1/2) values ranged from 
approximately 60–80 hours, with the exception of the 90mg QOD cohort.  At 90 mg 
QOD, apparent terminal t1/2 was assessable in one patient and was approximately 50 
hours.   
 
Clinical Efficacy/Pharmacodynamics 
 
Preliminary pharmacodynamic results in cancer patients indicate that phosphorylation of 
AKT in whole blood is substantially inhibited at all dose levels evaluated on the QOD 
and QW schedule.  Additionally, preliminary results indicate that substantial pAKT 
inhibition was demonstrated in tumor tissue at 60 mg QOD.  As there is a causal 
relationship between the development of hyperglycemia/hyperinsulinemia and 
mechanism of AKT inhibition, such events could potentially implicate pharmacodynamic 
activity of MK-2206.  In cancer patients, reversible grade 1/2 hyperglycemia was 
observed across all dose levels in a total of 59 patients.  Hyperinsulinemia occurred in 26 
patients who received MK-2206 60 mg QOD.  From a preliminary analysis, these adverse 
events (AEs) do not appear to be dose-dependent.  Neither hyperglycemia nor 
hyperinsulinemia was observed at any single dose in HVs.   
 
Thus far, no formal efficacy studies have been performed with MK-2206; however, in 
patients with advanced solid tumors, early indications of antitumor activity included 
substantial decreases in CA125 in some patients with ovarian cancer and PSA 
stabilization in some prostate cancer patients.  Minor RECIST responses, e.g., <30% 
decreases in tumor size, have also been observed in a patient with melanoma (16%), a 
patient with pancreatic cancer (23%), and in a patient with neuroendocrine tumor (20%).  
No partial responses, e.g., confirmed >30% decreases in tumor size, have been observed. 
 
Clinical Toxicology  
 
Preclinical efficacy and safety studies and preliminary safety data from the clinical 
studies support the use of MK-2206 via the oral route, both as monotherapy and in 
combination with other anticancer agents.   
 
Overall, MK-2206 has been generally well-tolerated when administered as a single PO 
dose (0.25-100 mg) to HVs, or to cancer patients as the 30-60 mg PO dose on the QOD 
schedule and the 90-200 mg PO dose on the QW schedule.  Mild-to-moderate skin rash 
was observed in 21 of 42 patients (50.0%) and severe skin rash was observed in 5 of 42 
patients (11.9%) at the dose of 60 mg QOD.   Skin rash resolved following the 1- to 2- 
week therapy break.  The higher doses evaluated in oncology patients (i.e., 75 and 90 mg 
QOD and 300 mg QW) were not tolerated and resulted in DLT of grade 3/grade 4 skin 
rash.   
 


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16 
Mild to moderate mucositis and conjunctivitis were associated with rash.  The 
supportive-care measures included hydration, topical steroid preparations, oral 
corticosteroids, oral antihistamines, and oral antibiotics.  Other common AEs included 
nausea, fatigue, vomiting, and diarrhea.  These AEs were mild to moderate and in most 
cases were resolved by the standard supportive care and did not require therapy 
modifications.  Hyperglycemia and hyperinsulinemia, both expected mechanism-based 
AEs, were observed in approximately 76% and 57% of patients, respectively, receiving 
MK-2206 on the QOD schedule.  Episodes were generally mild, transient, and did not 
require therapeutic intervention.  Importantly, administration of insulin may not 
counteract MK-2206-induced hyperglycemia due to mechanism-based insulin resistance.  
In this case, hydration and oral antihyperglycemic agents can be used as the supportive-
care measures.  Grade 3 hyperglycemia occurred in 1 patient who received 60 mg QOD 
and required treatment with PO antihyperglycemic medication.  Grade 4 hyperglycemia 
was reported in one patient who received MK-2206 45 mg QOD in combination with 
erlotinib.  In addition to supportive care measures, blood glucose management included 
administration of insulin and PO antihyperglycemic medication.     
 
Grade 1/grade 2 prolongation of QTc-interval was observed in 14 out of 64 patients 
(21.9%) with available 12-lead ECG data.  Prolongations 30 msec but <60 msec 
occurred in 4 of these patients.  Grade 3 QTc prolongation was reported in one patient 
who received 135 mg QW.  Episodes of QTc interval prolongation were in general 
isolated with no apparent dependency on dose or exposure levels, and were not 
considered clinically significant by investigators and were not reported as adverse 
experiences.  Eleven patients experienced sinus bradycardia (<50 bpm) during Holter or 
ECG monitoring.  These events were asymptomatic and were not clinically significant.  
While a causal relationship between these events and administration of MK-2206 is 
uncertain, similar side effects were seen preclinically in conscious dogs.  Consequently, 
patients with a history or current evidence of heart disease should be excluded from 
enrollment on MK-2206 trials.  Standard 12-lead ECG measurements should be 
performed at the protocol-specified time-points.   
 
Developmental/Reproductive Toxicity 
Developmental and reproductive toxicity studies of MK-2206 have not been performed 
thus far.  MK-2206 was not tested in pregnant or breast-feeding women.  Women of 
child-bearing potential and men participating in clinical studies of MK-2206 must use 
appropriate contraception, including abstinence and double-barrier methods, throughout 
MK-2206 therapy.  In preclinical mutagenicity studies, MK-2206 was neither genotoxic 
or mutagenic. 
 
Drug Interactions 
No clinical drug interaction studies have been performed with MK-2206.  Oxidative 
metabolism of MK-2206 in human liver microsomes was catalyzed primarily by 
CYP3A4.  MK-2206 was not an inhibitor of the major CYPs.  Human hepatocyte 
induction data suggested a low potential as an inducer of CYP3A for MK-2206 at 
clinically relevant concentrations.  MK-2206 was shown to be a P-gp substrate. 
 


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17 
 
2.3 
Other Agent(s) 
 
Everolimus:   
 
RAD001 (everolimus) Everolimus is a novel oral derivative of rapamycin. Everolimus 
has been in clinical development since 1996 as an immunosuppressant in solid organ 
transplantation and has obtained marketing authorization (Certican®) for prophylaxis of 
rejection in renal and cardiac transplantation in a number of countries, including the 
majority of the European Union. Everolimus has been in development for patients with 
various malignancies since 2002. Everolimus is being investigated as an anticancer agent 
based on its potential to act: 
 
•  Directly on the tumor cells by inhibiting tumor cell growth and proliferation 
•  Indirectly by inhibiting angiogenesis leading to reduced tumor vascularity (via 
potent inhibition of tumor cell HIF-1 activity, VEGF production and VEGF-
induced proliferation of endothelial cells). The role of angiogenesis in the 
maintenance of solid tumor growth is well established, and the mTOR pathway 
has been implicated in the regulation of tumor production of proangiogenic 
factors as well as modulation of VEGFR signaling in endothelial cells. 
 
At weekly and daily schedules and at various doses explored, everolimus is generally 
well tolerated. The most frequent adverse events (rash, mucositis, fatigue and headache) 
associated with everolimus therapy are manageable. Non-infectious pneumonitis has been 
reported with mTOR inhibitors but is commonly low-grade and reversible.  
 
2.3.1  mTOR Pathway and Mechanism of Action 
At cellular and molecular level everolimus acts as a signal transduction inhibitor. 
Everolimus selectively inhibits mTOR (mammalian target of rapamycin), a key 
and a highly conservative serine-threonine kinase, which is present in all cells and 
is a central regulator of protein synthesis and ultimately cell growth, cell 
proliferation, angiogenesis and cell survival. mTOR is the only currently known 
target of everolimus (Reviewed in Boulay and Lane, 2007).  mTOR is 
downstream of PI3K/AKT pathway, a pathway known to be deregulated in a wide 
spectrum of human cancers (e.g. through loss/mutation of the PTEN negative 
regulator; through PI3K mutation/amplification; through AKT/PKB 
overexpression/overactivation; through modulation of TSC1/TSC2 tumor 
suppressors). In addition, activation of the PI3K/AKT/mTOR pathway is 
frequently a characteristic of worsening prognosis through increased 
aggressiveness, resistance to treatment and progression. The main known 
functions of mTOR include the following (Bjornsti and Houghton 2004; Boulay 
and Lane, 2007):  
•  mTOR functions as a sensor of mitogens, growth factors and energy and 
nutrient levels, facilitating cell-cycle progression from G1 to S phase in 
appropriate growth conditions.  


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•  The PI3K-mTOR pathway itself is frequently activated in many human 
cancers, and oncogenic transformation may sensitize tumor cells to mTOR 
inhibitors. 
 •  Through inactivating eukaryotic initiation factor 4E binding proteins (4E-
BP1) and activating the 40S ribosomal S6 kinases (i.e., p70S6K1), mTOR 
regulates translation of important massages, including those encoding the 
HIF-1 proteins, c-myc, ornithine decarboxylase, and cyclin D1, as well as 
ribosomal proteins themselves. 
•  The activation of mTOR pathway leads to the increased production of pro-
angiogenic factors (i.e., VEGF) in tumors and to tumor, endothelial and 
smooth muscle cell growth and proliferation. 
•  The regulation of mTOR signaling is complex and involves positive 
regulators, such as AKT that phosphorylate and inactivate negative regulators 
such as the Tuberous Sclerosis Complex (TSC1/TSC2).  
 
mTOR is represented by two structurally and functionally distinct multiprotein 
signaling complexes, mTORC1 (mTOR complex 1, rapamycin sensitive) and 
mTORC2 (mTOR complex 2, rapamycin insensitive) (Wullschleger, Loewith and 
Hall 2006). mTORC1 is mainly activated via the PI3 kinase pathway through 
AKT (also known as PKB, protein kinase B) and the tuberous sclerosis complex 
(TSC1/TSC2) (Bjornsti and Houghton 2004). Activated AKT phosphorylates 
TSC2, which lead to the dissociation of TSC1/TSC2 complex, thus inhibiting the 
ability of TSC2 to act as a GTPase activating protein. This allows Rheb, a small 
G-protein, to remain in a GTP bound state and to activate mTORC1. AKT can 
also activate mTORC1 by PRAS40 phosphorylation, thereby relieving the 
PRAS40-mediated inhibition of mTORC1 (Manning and Cantley 2007; Wang at 
al 2007). mTORC2 (mTOR complex 2) is activated through a currently unknown 
mechanism, possibly by receptor tyrosine kinase (RTK) signalling (Manning and 
Cantley 2007). It has been suggested that mTORC2 phosphorylates and activates 
a different pool of AKT, that is not upstream of mTORC1. PHLPP phospatase 
plays a role of a negative regulator. mTORC2 is rapamycin insensitive and is 
required for the organization of the actin cytoskeleton (Wullschleger, Loewith and 
Hall 2006). mTORC1-mediated signaling is subject to modulation by the 
macrocyclic lactone rapamycin and its derivatives, such as everolimus. Once 
these agents bind to the 12 kDa cytosolic FK506- binding protein immunophilin 
FKBP12, the resulting rapamycin- FKBP12 complexes bind to a specific site near 
the catalytic domain of mTORC1 and inhibit phosphorylation of mTOR 
substrates. As a consequence, downstream signaling events involved in regulation 
of the G1 to S-phase transition are inhibited. This mechanism is thought to be 
responsible for the immunosuppressive effects of rapamycin as well as its putative 
antineoplastic activity (Witzig, et al 2005). As many cancers are characterized by 
dysregulation of G1 transit (for example, overexpression of cyclin or cyclin-
dependent kinases), inhibition of mTOR becomes an intriguing target for inducing 
cytostasis (Bjornsti and Houghton 2004).  
 
 


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2.3.2  Preclinical Studies 
Pre-clinical investigations have demonstrated that everolimus is a potent inhibitor 
of the proliferation of a range of human tumor cell lines in-vitro with IC50s 
ranging from sub/low nM to μM concentrations, concentrations capable of being 
reached in patients at the doses used in clinical trials. Everolimus was shown to 
have activity in human tumor cell lines originating from lung, breast, prostate, 
colon, kidney, melanoma and glioblastoma. Everolimus was also shown to have 
activity in human pancreatic neuroendocrine cells, where induction of apoptosis 
was reported (Zitzmann, et al 2007), as well as in acute myeloid leukemia cells 
(Zeng, et al 2007), adult T-cell leukemia cells (Ikezoe, et al 2007), diffuse large B 
cell lymphoma cells (DLBCL; Wanner, et al 2006), pancreatic tumor cells 
(Tuncyurek, et al 2007), ovarian cancer cells (Treeck, et al 2006, Mabuchi, et al 
2007) and hepatocellular carcinoma cells (Sieghart, et al 2007). As a single agent, 
everolimus inhibited proliferation in three mantle cell lymphoma cell lines (Jeko1, 
SP49 and NCEB1) approximately 40–65% compared to control cells. This was 
associated with G1 cell-cycle arrest and reduced phosphorylation of the mTOR 
downstream target, 4E-BP1 (Haritunians, et al 2007). In a clonogenic assay using 
cells derived from 81 patient-derived tumor xenografts never cultured in vitro (11 
human tumor types with 3 to 24 tumors each: bladder, colon, gastric, NSCLC 
[adeno, squamous epithelium and large cell], SCLC, breast, ovary, pancreatic, 
renal, melanoma, and pleuramesothelioma), everolimus inhibited colony 
formation in a concentration-dependent manner. In addition, normal hematopoetic 
stem cells were insensitive to everolimus, with an IC50 about 15 fold higher than 
the tumor lines. Everolimus also inhibits the proliferation of human umbilical vein 
endothelial cells (HUVECS), with particular potency against VEGF induced 
proliferation. The inhibition of endothelial proliferation and antiangiogenic 
activity of everolimus was confirmed in vivo, as everolimus selectively inhibited 
VEGF-dependent angiogenic response. Mice with primary and metastatic tumors 
treated with everolimus showed a significant reduction in blood vessel density 
when compared to controls at well tolerated doses. Additionally, activity in a 
VEGF-impregnated s.c. implant model of angiogenesis and reduced vascularity 
(vessel density) of everolimus-treated tumors (murine melanoma) provided 
evidence of in vivo effects of angiogenesis. Everolimus also inhibits tumor growth 
in-vivo in xenografted, syngeneic and orthotopic animal models, residing longer 
in tumor tissue than in plasma and demonstrating high tumor penetration in a rat 
pancreatic tumor model. These effects occurred within the dose range of 2.5 to 10 
mg/kg p.o. daily. Typically, the antitumor activity of everolimus monotherapy 
was that of reduction of tumor growth rates rather than producing regressions or 
stable disease. Everolimus, administered p.o., was a potent inhibitor of tumor 
growth and well tolerated in:  
 
•  s.c. mouse xenograft model, established from a variety of tumor cell lines of 
diverse histotypes (NSCLC, pancreatic, colon, melanoma, epidermoid), 
including a Pgp170 over-expressing multi-drug resistant tumor line 
•  a series of low-passage tumor xenografts established directly from human 
tumor material, maintained only in vivo and considered highly predictive of 


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therapeutic outcome in patients. These included breast (5 lines), colorectal (9 
lines), gastric (3 lines), lung (22 lines including adenocarcinomas, epidermoid 
cell, large cell and small cell histotypes), melanoma (6 lines), ovarian (4 
lines), pancreatic (3 lines) and renal (6 lines) 
•  two syngeneic models (CA20948 rat pancreatic, B16/Bl6 mouse orthotopic 
melanoma) 
 
Taken together, these data indicate the broad anti-proliferative potential of 
everolimus. It is not clear which molecular determinants predict responsiveness of 
tumor cells to everolimus. Molecular analysis has revealed that relative sensitivity 
to everolimus in vitro correlates with the degree of phosphorylation (activation) of 
the AKT/PKB protein kinase and the S6 ribosomal protein. PTEN status alone 
may not be predictive of everolimus relative in vitro sensitivity, however in some 
cases (i.e., GBM) there is also a correlation with PTEN status. In preclinical 
models, the administration of everolimus is associated with reduction of protein 
phosphorylation in target proteins downstream of mTOR, notably phosphorylated 
S6 (pS6) and p4EBP1, and occasionally with an increase in phosphorylation AKT 
(pAKT). 
 
2.3.3  Pre-clinical Safety 
In safety pharmacology studies, everolimus was devoid of relevant effects on vital 
functions including the cardiovascular, respiratory and nervous systems. 
Everolimus had no influence on QT interval prolongation. Furthermore, 
everolimus showed no antigenic potential. Although everolimus passes the blood-
brain barrier, there was no indication of relevant changes in the behavior of 
rodents, even after single oral doses up to 2000mg/kg or after repeated 
administration at up to 40 mg/kg/day. Based on these findings, the potential of 
everolimus to affect vital functions in patients is considered to be low. 
 
Everolimus is considered to have no genotoxicity or carcinogenicity potential. All 
significant adverse events observed in preclinical toxicology studies with 
everolimus in mice, rats, monkeys and minipigs were consistent with its 
anticipated pharmacologic action as an antiproliferative and immunosuppressant 
and at least in part reversible after a 2- or 4-week recovery period with the 
exception of the changes in male reproductive organs, most notably testes.  Ocular 
effects (lenticular disorders) observed in rats were not observed in any other 
species and are considered to be a species specific disorder.  
 
2.3.4  Clinical experience 
Everolimus Pharmacokinetics 
Everolimus is rapidly absorbed with a median tmax of 1-2 hours. The 
bioavailability of the drug is believed to be 11% or greater. The AUC0-τ is dose-
proportional over the dose range between 5 to 70 mg in the weekly regimen and 5 
and 10 mg in the daily regimen. Cmax is dose-proportional between 5 and 10 mg 
for both the weekly and daily regimens. At doses of 20 mg/week and higher, the 
increase in Cmax is less than dose-proportional. The coefficient of variation 


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between patients is approximately 50%. Trough levels (24 hour post-dose) 
correlate well with AUC0-τ at steady-state during daily administration. In whole 
blood, at a daily dose of 10 mg, about 20% of everolimus is confined in plasma 
with 26% being unbound. The remaining 80% is sequestered in blood cells. 
Everolimus is extensively metabolized in the liver and eliminated in the bile. 
Major metabolites are inactive. Elimination half-life is approximately 30 hours. 
The clearance of everolimus is approximately halved in patients with mild-
moderate hepatic impairment (Child-Pugh Class A or B), while renal impairment 
has little or no impact on the pharmacokinetics of everolimus. Age, weight and 
gender in the adult population do not affect the pharmacokinetics of everolimus to 
a clinically relevant extent. The clearance of everolimus is reduced in children. 
Pharmacokinetic characteristics are not notably different between Caucasian and 
Japanese subjects, whereas in Black patient populations pharmacokinetic studies 
have shown an average 20% higher clearance.  A high-fat meal altered the 
absorption of everolimus with 1.3 hour delay in tmax, a 60% reduction in Cmax 
and a 16% reduction in AUC. Everolimus is a substrate of CYP3A4 and a 
substrate and a moderate inhibitor of the multi-drug efflux pump P-glycoprotein 
(PgP, MDR1, ABCB1). Hence, its metabolism is sensitive to drugs which modify 
these enzymes (substrates, inducers, or inhibitors of these enzymes). Competitive 
inhibition could occur when everolimus is combined with drugs which are also 
CYP3A4 or Pglycoprotein substrates. Appendix C lists examples of clinically 
relevant CYP3A inhibitors and inducers and a list of P Glycoprotein substrates 
can be accessed at the following link: http://www.genemedrx.com/PGPtable.php.  
Please refer to Appendix C and/or the everolimus prescribing information for 
more information on the concomitant use of CYP3A4 inhibitors/inducers and 
other medications. 
 
Everolimus Pharmacodynamic Studies 
Pharmacokinetic/pharmacodynamic modeling based on inhibition of the 
biomarker p70S6 kinase 1 [S6K1] in peripheral blood mononuclear cells 
[PBMC]) suggests that 5-10 mg daily should be an adequate dose to produce a 
high-degree of sustained target inhibition ([Study C2101] / [Study 2102], Lane, et 
al 2003). Furthermore, molecular pharmacodynamic (MPD) studies, using 
immunocytochemistry (IHC) in biopsied tumor tissue, assessed the degree of 
inhibition and its duration for pS6, p4E-BP1 and pAKT expression with the daily 
and weekly dosing. There was high inhibition of the downstream markers S6K1 
and 4E-BP1 at 5mg/day, which was complete at 10 mg/day, while preliminary 
results suggest increase in pAKT  expression with maximal effect at 10 mg daily 
([Study C2107], Tabernero, et al 2005). 
 
Clinical Experience with Everolimus 
Everolimus has been investigated as a component of multi-drug 
immunosuppression in solid organ transplantation since 1996 and was approved 
for the indication of prophylaxis of organ rejection in adult patients receiving an 
allogeneic renal or cardiac transplant on 8 Jul 2003 by the European Union under 
the trade name of Certican®. The most frequent adverse drug reactions in this 


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context are highly specific to the transplant context. However, certain events are 
generalizable, most notably myelosuppression, skin disorders and increases in 
blood lipid levels. Everolimus has been in development for patients with cancer 
since 2002. Approximately 4000 patients with various malignancies have been 
treated in either Novartis sponsored or non-Novartis sponsored, and 3 healthy 
volunteer clinical studies as of 31 Aug 2008. Overall, Novartis sponsored a total 
of 28 studies of everolimus administered either as single-agent (n=13), or in 
combination with other anti-tumor agents (n=15). Ongoing or completed 
Investigator sponsored studies also enrolled over 1000 patients globally. 
 
Eight single-agent Novartis sponsored trials have or are being conducted in 
various advanced malignancies. Five Phase I studies evaluated several escalating 
doses with either weekly or daily administration (Studies C2101/02, C2106, 
C2107, C1101) of everolimus with the  objective to identify an optimal regimen 
and dosage, based on safety, pharmacokinetics and knowledge of the drug’s 
molecular effects on various tumors. The 10 mg/day and 50-70 mg/week dosages 
were proposed for further studies, when using everolimus as a single agent, and as 
a target maximum dose in combination studies. In addition the Phase I studies, 
conducted in prostate cancer (Study C2106) and in Japanese patients with 
advanced cancers (Study C1101), evaluated the safety and the molecular changes 
in tumor, associated with the administration of everolimus.  Two Phase II 
monotherapy studies were designed to evaluate the safety and efficacy of a single 
dose of 10 mg administered daily including Study C2235 in advanced NSCLC 
(n=81) and Study C2239 in advanced pancreatic neuroendocrine tumors (n=160). 
A Phase III, randomized, double blind, placebo controlled study in patients with 
mRCC who progressed on a VEGFr TKI demonstrated that everolimus, 
administered daily at an oral dose of 10 mg, was superior to placebo for the 
primary endpoint of progression free survival. Median PFS was prolonged from 
1.9 months for patients receiving placebo to 4.9 months for everolimus treated 
patients, assessed by central independent review blinded to clinical data (hazard 
ratio 0.33, 95% CI 0.25-0.43, p<0.001) (Kay et al, 2009). On 30 March 2009 
everolimus was approved for use in the United States for the treatment of patients 
with advanced renal cell carcinoma after failure of treatment with sunitinib or 
sorafenib.  Overall, the most frequent adverse effects suspected to be related to 
everolimus have been stomatitis, rash, anemia, fatigue, asthenia, diarrhea, 
anorexia, nausea, hypercholesterolemia, mucosal inflammation, vomiting, 
hypertriglyceridemia, cough, peripheral edema, dry skin, epistaxis, pruritus and 
dyspnea. The most common Grade 3 or 4 adverse reactions suspected to be 
related to treatment were anemia, infections, hyperglycemia, stomatitis, fatigue, 
lymphopenia, hypercholesterolemia, pneumonitis, and elevated 
gammaglutamyltransferase concentrations. Non-infectious low-Grade (Grade 1/2) 
pneumonitis has led to development of treatment guidelines for the disorder 
(Section 6, Table 5). The primary DLT has been severe (Grade 3) stomatitis, and 
occasionally fatigue, hyperglycemia, and neutropenia.  
 
 


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2.3.5  Everolimus Safety Profile 
Adverse events most frequently observed with everolimus are rash, stomatitis/oral 
mucositis, fatigue, headache, anorexia, nausea, vomiting, and diarrhea. Infections 
have not been notably frequent or severe. Non-infectious pneumonitis has also 
been observed. The majority of these AEs have been of mild to moderate severity 
(CTC grade 1-2). Overall, the most frequently observed laboratory abnormalities 
include reduced blood counts, hyperlipidemia mostly reported as 
hypercholesterolemia and/or hypertriglyceridemia. The principal DLT in Phase 1 
trials has been Grade 3 stomatitis. For guidance on management of stomatitis 
refer to Section 6. Hyperlipidemia was reported as a serious adverse reaction. It is 
a recognized side-effect of rapamycins. Use of lipid-lowering drugs should be 
associated with dietary recommendations. Monitoring of blood lipid levels 
requires patients to be fasting so that this aspect must be verified when 
interpreting results. For guidance on management of hyperlipidemia refer to 
Section 6. Hyperglycemia was reported as a serious adverse reaction. Similarly, 
the fasting state of patients should be verified when interpreting results. For 
guidance on management of hyperglycemia refer to Section 6. Pneumonitis is a 
recognized adverse effect of rapamycins (sirolimus, temsirolimus, and 
everolimus). Numerous case reports in the literature suggest that rapamycin-
associated pneumonitis is relatively unaggressive, limited in extent, and reversible 
upon drug discontinuation. The term ‘pneumonitis’ is used here to describe non-
infectious, non-malignant infiltration in the lungs, which is evident radiologically. 
More precise diagnosis should follow histocytological examination following 
lung biopsy, generally during bronchoscopy which may or may not be 
symptomatic. Advice on the management of pneumonitis has been provided in 
Section 6 (table 5). 
 
In oncology studies with everolimus, severe pneumonitis suspected as drug-
related has been reported as a serious adverse event on 13 occasions and 
additionally in the following associated preferred terms including acute 
respiratory distress syndrome (n=2), alveolitis (n=1) and allergic alveolitis (n=1), 
interstitial lung disease (n=10), lung infiltration (n=23), cryptogenic organizing 
pneumonia, lung consolidation, pulmonary alveolar hemorrhage, pulmonary 
toxicity and pulmonary fibrosis (n=1, each). One fatal case of drug-related 
pneumonitis was reported for a patient with metastatic infiltrating ductal 
carcinoma of the breast treated with 10 mg/day, which developed approximately 
two months after starting everolimus. Cytology for both the pleural and 
pericardial fluids was positive for malignancy. The death was considered possibly 
related to the underlying late stage tumor and study drug. Additionally, one 
patient treated with 10 mg/day died due to severe acute respiratory distress 
syndrome and septic shock. Thoracic CT scan demonstrated condensation in the 
majority of the left lower lobe and frosted glass appearance in the left upper lobe, 
lingula, and right lung. 
 
Along with the cases of non-infectious pneumonitis, serious opportunistic 
infections have also been reported in cancer patients treated with everolimus: 


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mycobactrium, aspergillus, and fatal candidal sepsis, and fatal pneumocystis 
carnii in particular. Because everolimus, as other rapamycins, inhibits 
proliferation of activated lymphocytes and reduces neutrophil counts, treatment 
with everolimus must be considered as predisposing patients to the risk of 
infection. This risk will be higher in patients severely immunocompromised 
because of their underlying disease and/or co-medications. Outcome may be fatal 
in case of serious infections. A reduction in blood cell counts is frequent when 
everolimus therapy is initiated. Without clinical significance and infrequently, 
anemia and thrombocytopenia have been reported. In heavily pretreated patients 
with aggressive lymphoma, the incidence of grade 3 anemia, neutropenia, and 
thrombocytopenia was reported to be 11%, 16%, and 30%, respectively. Serious, 
suspected drug related hemorrhages have been exceptional. Nevertheless, 
everolimus should be considered as predisposing patients to hemorrhage, 
potentially fatal, should they develop severe drug related thrombocytopenia. 
Discrete, reversible changes in liver enzymes have been found to occur in 
numerous patients during treatment with everolimus in oncology clinical studies, 
and in a study in rheumatoid arthritis. In oncology studies, these changes may be 
evident only in patients without severe underlying morbidity. The increase in 
transaminases (AST and ALT) generally appears after 4 weeks of treatment. In all 
but a few cases it does not exceed Grade 1 (≤ 2.5 x ULN). Similarly, mild 
increases in alkaline phosphatases can coexist. Spontaneous corrections or 
intermittent correction with continued treatment can occur. Serum bilirubin is not 
increased. In studies of patients with advanced cancers, clinically relevant 
changes in liver enzymes have been invariably associated with the presence of 
liver metastases and/or progression of the underlying cancer. Renal failure has 
been reported in five suspected cases to date. One patient with no alternative 
explanation made a complete recovery following study drug adjustment and no 
treatment/therapy for the event. The rest or the patients had concurrent 
morbidities, which might have contributed to the reported events. 
Hypophosphatemia, hypomagnesemia, hyponatremia and hypocalcemia have 
been reported as serious adverse reactions. Electrolytes should be monitored in 
patients treated with everolimus. Table 4 and 5 provide general recommendations 
for the management of patients, with suspected drug toxicities while on treatment 
with everolimus as single-agent therapy.  
 
 
2.4 
Rationale 
 
Several studies show that upregulation of the PI3K pathway is associated with poorer 
prognosis in patients with nonmetastatic RCC.   Our data show that RCC patients treated 
with anti-VEGF therapy who have upregulation of components of the PI3K pathway have 
shorter PFS. In an 80 patient CTEP sponsored study of patients who received sorafenib or 
sorafenib plus IFN, AKT S473 was the single strongest predictor for clinical outcome in 
a panel of clinical and tissue variables.  Similarly, analysis of nephrectomy samples in 
patients who received presurgical bevacizumab showed that upregulation of AKT was 
associated with a shorter PFS and poorer overall survival.   We hypothesize that blockade 


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of AKT in patients who are refractory to anti VEGF therapy will eliminate one of the key 
drivers of tumor growth and proangiogenic signaling, and will result in prolongation of 
PFS. 
 
2.5 
Correlative Studies Background 
 
Tissue Microarrays (TMA) to assess PI3K pathway protein levels:  We have 
extensive experience in the generation and analysis of TMA in patients with RCC.  Our 
recently published CTEP sponsored randomized phase II study of sorafenib vs sorafenib 
plus IFN used this technique on 40 formalin fixed, paraffin embedded nephrectomy 
specimens from patients on the study.  We hypothesize that (1) upregulated AKT in 
nephrectomy specimens, including T308 and especially S473, will predict for response to 
MK2206 and (2) patients with baseline upregulated S473 will not show short PFS after 
treatment with the TORC1 inhibitor everolimus.  
 
We assume that patterns seen in primary tumors are reflective of those expressed in 
metastatic sites.  This assumption is supported by evidence that the karyotype and 
transcriptome is relatively similar when primary and metastatic disease is compared, and 
by unpublished observations from our group that protein expression in primary and 
metastatic sites is the same.  
 
Cytokines and Angiogenesis Factors (CAF) in RCC:  Analysis of the circulating 
miroenvironment will provide insight into baseline and induced biomarkers associated 
with response and resistance to AKT inhibition.  We have analyzed CAF from patient on 
the CTEP sorafenib trial, and have demonstrated biologically plausible associations with 
several factors, including VEGF and osteopontin.  A five factor signature permitted 
discrimination between patients who benefitted from sorafenib plus IFN versus patients 
who benefitted from sorafenib monotherapy (Clin Ca Res, submitted). The purpose of the 
current study is to generate a similar set of observations in patients receiving TORC1 or 
AKT blockade.   
 
We hypothesize that baseline and induced levels of CAF will be predictive for a response 
signature that identifies individuals who benefit from AKT blockade.  Comparison 
between patterns in patients who receive an AKT blocking agent versus those who 
receive a TORC1 blocking agent will provide valuable information on the endocrine 
effects of AKT versus TORC1 blockade.  These patterns may provide mechanistic insight 
into downstream pathways differentially affected by these two agents.   
 
Virtual Karyotyping as a Predictive Biomarker in RCC: RCC karyotypic changes 
have been associated with clinical outcome in primary RCC.    Preliminary data suggest 
that a specific karyotypic profile is associated with response and resistance to 
antiangiogenic therapy (abstracts, manuscript in preparation).  Evaluation of 
chromosomal regions to elucidate mechanisms behind the karyotypic observations is 
underway.  The purpose of the current study is to confirm our observations in a cohort of 
patients previously treated with anti-VEGF therapy, and to determine whether karyotypic 
patterns are predictive for response or resistance in TORC1 or AKT blocking agents.   


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We hypothesize that (1) Patients who showed a short PFS on prior anti-VEGF therapy 
will have a distinct karyotype, (2) These patients will show benefit to AKT blocking 
agents, and (3) Further karyotypic discrimination will be possible between patients who 
benefit from AKT blockade versus mTOR blockade. 
 
 
3. PATIENT SELECTION 
 
3.1 
Eligibility Criteria  
 
3.1.1 Patients must have histologically or cytologically confirmed metastatic or 
unresectable RCC.  All histologies are permitted.  Patient should have undergone 
nephrectomy. 
 
3.1.2 Patients must have measurable disease, defined as at least one lesion that can be 
accurately measured in at least one dimension (longest diameter to be recorded for 
non-nodal lesions and short axis for nodal lesions) as ≥20 mm with conventional 
techniques or as ≥10 mm with spiral CT scan.  See Section 11 for the evaluation of 
measurable disease. 
 
3.1.3 Patients must have received, and progressed on an anti-VEGF therapy, including 
bevacizumab, sorafenib, sunitinib or pazopanib.   
 
3.1.4 Because no dosing or adverse event data are currently available on the use of MK-
2206 or everolimus in patients < 18 years of age, children are excluded from this 
study but will be eligible for future pediatric phase 2 trials. 
  
3.1.5 ECOG performance status ≤1. 
 
3.1.6 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 
• total bilirubin 
 
 
 
within normal institutional limits 
• AST(SGOT)/ALT(SGPT) 
≤ 2.5 × institutional upper limit of normal 
• Serum creatinine  
 
 
≤ 1.5 x ULN 
 
3.1.7 INR and PTT ≤ 1.5 x ULN. Therapeutic anticoagulation with warfarin is allowed if 
target INR ≤ 3 on a stable dose of warfarin or on a stable dose of LMW heparin for 
> 2 weeks at time of randomization.  
 


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3.1.8 The effects of MK-2206 and/or everolimus on the developing human fetus at the 
recommended therapeutic dose are unknown.  For this reason, women of 
childbearing potential and men must use two forms of contraception (hormonal or 
barrier method of birth control; abstinence) prior to study entry, for the duration of 
study participation and for 8 weeks after the last dose of study drug.  Should a 
woman become pregnant or suspect she is pregnant while she or her partner is 
participating in this study, the patient should inform the treating physician 
immediately.  
 
3.1.9 Ability to understand and the willingness to sign a written informed consent 
document. 
 
3.1.10 Serum pregnancy test in female patients of childbearing potential must be negative 
within 24 hours of enrolling on this study. 
 
3.2 
Exclusion Criteria 
 
3.2.1 Patients who received oral TKIs (sorafenib, sunitinib, or pazopanib) within 2 weeks 
prior to entering the study, radiotherapy, immunotherapy or chemotherapy within 4 
weeks prior to entering the study, bevacizumab within 4 weeks prior to entering the 
study, or those who have not recovered from adverse events due to agents 
administered more than 4 weeks earlier (recovered to ≤ Grade 1). 
 
3.2.2 Patients may not be receiving any other investigational agents.  Patients may not 
have received an mTOR inhibitor.   
 
3.2.3 Patients with known brain metastases should be excluded from this clinical trial 
because of their poor prognosis and because they often develop progressive 
neurologic dysfunction that would confound the evaluation of neurologic and other 
adverse events. 
 
3.2.4 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to MK-2206 or other agents used in the study. 
  
3.2.5 Patients receiving any medications or substances that are strong inhibitors or 
inducers of CYP 450 3A4 are ineligible.  Lists including medications and 
substances known or with the potential to interact with the CYP 450 3A4 
isoenzymes are provided in Appendix C. 
 


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3.2.6 Patient should have a Hemoglobin A1C value of < 8%.  Preclinical studies 
demonstrated the potential of MK-2206 for induction of hyperglycemia in all 
preclinical species tested.  Studies also demonstrate a risk of hyperglycemia, 
hyperlipidemia and hypertriglyceridemia associated with everolimus therapy. 
Patients with diabetes or in risk for hyperglycemia, hyperlipidemia and/or 
hypertriglyceridemia should not be excluded from trials with MK-2206 or 
everolimus, but the patient should be well controlled on oral agents (recent (i.e. 
within 3 months) HbA1C ≤ 7.0) before the patient enters the trial. 
  
3.2.7 Preclinical studies indicated transient changes in QTc interval during MK-2206 
treatment.  Prolongation of QTc interval is potentially a safety concern while on 
MK-2206 therapy.  Cardiovascular: baseline QTcF > 450 msec (male) or QTcF > 
470 msec (female) will exclude patients from entry on study.  A list of medications 
that may cause QTc interval prolongation are listed in Appendix D, and should be 
avoided by patients entering on trial. 
  
3.2.8 Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that would limit compliance with 
study requirements. 
  
3.2.9 Pregnant women are excluded from this study because MK-2206 and/or everolimus 
are agents with the potential for teratogenic or abortifacient effects.  Because there 
is an unknown but potential risk for adverse events in nursing infants secondary to 
treatment of the mother with MK-2206 and/or everolimus, breastfeeding should be 
discontinued if the mother is treated with MK-2206 or everolimus. 
 
3.2.10 HIV-positive patients on combination antiretroviral therapy are ineligible because 
of the potential for pharmacokinetic interactions with MK-2206 or everolimus.  In 
addition, these patients are at increased risk of lethal infections when treated with 
marrow-suppressive therapy. 
 
3.2.11  Individuals who are diagnosed with an intercurrent cancer are excluded, with the 
exception of non-melanoma skin cancers, and other cancers where curative 
treatment was completed at least two years ago. 
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial. 
 
 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
 
Males 
 
Total 
Hispanic or Latino 
2 
+ 
12 
= 
14 


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29 
Not Hispanic or Latino 
28 
+ 
72 
= 
100 
Ethnic Category: Total of all subjects 
               30 (A1) + 
             84 
(B1) = 
              114 (C1) 
Racial Category 
 
American Indian or Alaskan Native 
1 
+ 
1 
= 
2 
Asian 
0 
+ 
0 
= 
0 
Black or African American 
6 
+ 
6 
= 
12 
Native Hawaiian or other Pacific 
Islander 
0 
+ 
0 
= 
0 
White 
23 
+ 
77 
= 
100 
Racial Category: Total of all subjects 
               30 (A2) + 
             84 
(B2) = 
              114 (C2) 
 
(A1 = A2) 
 
(B1 = B2) 
 
(C1 = C2) 
 
 
4. REGISTRATION PROCEDURES 
 
 
4.1 
General Guidelines 
 
See Appendix K:  Multi-Center Study Management Plan 
 
Following registration, patients should begin protocol treatment within 5 days.  Issues that would 
cause treatment delays should be discussed with the Principal Investigator.  If a patient does not 
receive protocol therapy following registration, the patient’s registration on the study may be 
canceled.  The Study Coordinator should be notified of cancellations as soon as possible. 
 
Except in very unusual circumstances, each participating institution will order DCTD-supplied 
agents directly from CTEP.  Agents may be ordered by a participating site only after the initial 
IRB approval for the site has been forwarded by the Coordinating Center to the CTEP PIO 
(PIO@ctep.nci.nih.gov) except for Group studies. 
 
4.2 
Registration Process 
 
Before an institution may begin participation in a M.D. Anderson protocol, all the required steps 
outlined in Section 3.3 of Appendix K concerning regulatory documents, must be fulfilled. 
 
Prior to protocol enrollment and initiation of treatment, subjects must sign and date an 
Institutional Review Board (IRB) approved consent form. Patients at participating institutions 
should be registered with their institutional central registration first, following each institution's 
established policies. All patients must then be registered in the M.D. Anderson database, Clinical 
Oncology Research System (CORe) before beginning treatment.  CORe is a clinical research 
information management system supporting clinical research trials at U.T. M.D. Anderson 
Cancer Center and collaborative sites across the nation. 
 
At the time of registration, the registrant will be requested to verify the patient’s eligibility in 


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30 
CORe by answering a series of inclusion/exclusion protocol questions and the name of the 
registering physician.  Once patient eligibility has been established, the patient will then be 
automatically registered and randomized to the appropriate treatment arm. Therapy may then be 
initiated per protocol guidelines. 
 
Please see Section 3.3 of Appendix K for registration requirements and data collection 
guidelines. 
 
 
5. TREATMENT PLAN 
 
5.1 
Agent Administration 
 
Patients will be randomized 2:1 to one of two treatment arms (i.e. Arm A: MK-2206; Arm B: 
Everolimus). Treatment will be administered on an outpatient basis.  Reported adverse events 
and potential risks for MK-2206 and everolimus are described in Section 7.  Appropriate dose 
modifications for MK-2206 and everolimus are described in Section 6.  No investigational or 
commercial agents or therapies other than those described below may be administered with the 
intent to treat the patient's malignancy. 
 
The patient will be requested to maintain a medication diary of each dose of medication.  The 
medication diary will be returned to clinic staff at the end of each course. Patients should be 
instructed to record doses as they take them and not to enter them in batches at a later time. 
 
5.1.1 MK-2206 (Arm A) 
 
There is no specific guidance available regarding overdose due to the lack of clinical 
experience.  In case of an acute overdose, it is recommended that activated charcoal be 
administered orally to reduce the absorption of MK-2206. 
 
MK-2206 is an oral drug that may be administered once weekly (QW).  Patients should 
take MK-2206 at a starting dose of 200mg PO once weekly 2 hours before or after a 
meal.  The phase 1 clinical pharmacology study of MK-2206 in volunteers included a 
panel of 8 patients who were administered MK-2206 after a high-fat breakfast.  The 
results indicated a moderate increase in AUC and a slight increase in Cmax relative to 
that of fasted patients.  
 
A study cycle will be 4 weeks in length.  Patients who are progression free after 1 year 
may be given a 12 week (+/- 7 days) study drug supply. 
 
5.1.2 Everolimus (Arm B) 
 
Everolimus is an oral drug that will be administered once daily. Patients should take 
everolimus at a staring dose of 10 mg orally once daily. Patients will be instructed to take 
everolimus in the morning, at the same time each day. 
 


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A study cycle will be 4 weeks in length. 
 
5.2 
Screening and Evaluation On-Study 
 
Within four weeks of study entry: 
• All the participants must have signed a consent form agreeing to participate in the 
study. 
• Radiological studies shall include a chest X-ray, and CT scans of the chest and 
abdomen for the baseline tumor measurement, a CT or MRI of the brain, and a bone 
scan. Appropriate additional studies should be obtained to fully define the extent 
and severity of existing or suspected malignant disease. 
• A MRI of the spine should be obtained, if there is suspicion of evolving cord or 
nerve root compression. Spinal cord or nerve root compression syndromes should 
be managed before trial entry. 
• A skeletal survey and a CT scan of the pelvis will be ordered as clinically indicated. 
• A 12-lead electrocardiogram  
 
Within two weeks of study entry: 
• All patients must undergo a complete history and physical examination, including 
vital signs, ECOG performance status, recent weight loss, height, and current 
weight. 
• Concurrent non-malignant disease and medical therapy must be documented. On-
study forms must be filled out completely. 
• All prior anti-cancer treatment must be recorded in proper detail. Any residual 
toxicity from prior therapies should be recorded by using the grading schema in 
NCI Common Toxicity Criteria v4.0. 
• Patient’s MSKCC prognostic criteria will be recorded. (Appendix J). 
• Laboratory studies shall include CBC w/differential, platelet count,  chemistry 
panel (total protein, albumin,  alkaline phosphatase, AST and/or ALT, calcium, 
LDH, total bilirubin, BUN, creatinine, phosphorus, uric acid, sodium, potassium, 
chloride, carbon dioxide, magnesium, glucose), amylase, lipase, PT and PTT, and 
urinalysis (pH, specific gravity, ketones, RBC, WBC, bilirubin, and protein). T4, 
TSH will be obtained. Hemoglobin A1C, fasting glucose, lipid panel and 
triglycerides will be obtained. Serum pregnancy test in female patients of 
childbearing potential will also be included and must be negative within 24 hours of 
enrolling on this study. 
 
Optional studies with patient consent: 
• Nephrectomy blocks will be acquired to: a) generate tissue microarray (TMA) to 
stain for PI3K pathway components and other biologically relevant pathways and 
molecules and b) perform virtual karyotyping.  
• Baseline blood will be drawn for a) plasma and serum analysis of cytokines and 
angiogenesis factors b) circulating monocytic cells.   
 
 


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Evaluation During Treatment: 
On-study evaluations will consist of the following study activities every four weeks +/- 
four days (Patients who are progression free after 1 year may have the following 
performed every 12 weeks +/- 7days): 
• History and physical exam by physician, or mid-level provider at each scheduled 
visit. 
• Vital signs (including weight) and ECOG performance status 
• Serum chemistry including total protein, albumin,  alkaline phosphatase, AST 
and/or ALT, calcium, LDH, total bilirubin, BUN, creatinine, phosphorus, uric acid, 
sodium, potassium, chloride, carbon dioxide, magnesium, and glucose at each 
scheduled visit (+/- 4 days). Hematology including CBC with differential and 
platelet counts and PT and PTT at each scheduled visit (+/- 4 days). T4, TSH, will 
be obtained at each scheduled visit (+/- 4 days). Amylase and lipase will be 
repeated at each scheduled visit as clinically indicated. Fasting lipid panel and 
glucose will be done every 4 weeks for the first 8 weeks and every 8 weeks 
thereafter. Cycle 1 Day 1 blood tests will not be done if screening labs were done in 
the previous 7 days. 
• Serum glucose level monitoring for patients every 7 days +/- 2 days for patients on 
MK2206 during the first cycle of therapy.  These measurements do not have to be 
performed at the study site, but data must be provided to the study team by the 
patient.   
• Hemoglobin A1c levels need to be monitored at the beginning of each cycle for 
patients on MK2206 who require antihyperglycemic medication.  
• Record concomitant medications at each scheduled visit. 
• Monitor for adverse events. Treatment-related toxicity (acute and cumulative) will 
be performed every scheduled visit. 
• On C1D1 only, patients randomized to MK-2206 will have an ECG within 4 hours 
of taking study drug. 
 
Optional studies with patient consent:  
• Blood will be drawn for a) plasma and serum analysis of cytokines and 
angiogenesis factors and b) circulating monocytic cells.   
 
In addition to the above, the following will be performed every eight weeks+/- 7 days 
(Patients who are progression free after 1 year may have the following performed every 
12 weeks +/- 7days):  
• Repeat radiologic studies (CT, MRI, Chest x-ray and bone scan as indicated) to 
evaluate disease progression or response (in accordance with restaging of disease). 
Studies to confirm a complete response or document progressive disease will be 
performed as needed. 
• 12-lead electrocardiogram (ECG)  
 
 
 


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33 
 
End of Treatment 
 
The following study activities will be completed after treatment has been discontinued for 
any reason: 
• Physical exam. 
• Vital Signs including weight 
• Radiologic assessment and assessment of response. 
• 12-lead electrocardiogram. 
• Urinalysis to include: pH, specific gravity, ketones, RBC, WBC, bilirubin, protein, 
and glucose. 
• Serum chemistry including total protein, albumin,  alkaline phosphatase, AST 
and/or ALT, calcium, LDH, total bilirubin, BUN, creatinine, phosphorus, uric acid, 
sodium, potassium, chloride, carbon dioxide, magnesium, and glucose 
• TSH, T4. 
• Hematology to include: CBC with differential and platelet count, PT and PTT. 
• Record for concomitant medications. 
• Monitor for adverse events. 
 
Optional studies with patient consent:  
• Blood will be drawn for a) plasma and serum analysis of cytokines and 
angiogenesis factors b) circulating monocytic cells 
 
 
5.3 
General Concomitant Medication and Supportive Care Guidelines 
 
Because MK-2206 is metabolized by CYP3A4, 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.  A list of agents known to interact with the 
CYP3A4 isoform is listed in Appendix C. 
 
Drugs known that may prolong the QTc interval should be avoided. 
 
Everolimus is a substrate of CYP3A4 and a substrate and inhibitor of P-glycoprotein. Everolimus 
metabolism may be affected by drugs that are substrates or strong inhibitors or inducers of 
CYP3A4 or P-glycoprotein.  A list of agents known to interact with the CYP3A4 and P-
glycoprotein are listed in Appendix C. 
 
 
5.4 
Definition of Dose-Limiting Toxicity  
 
A dose limiting toxicity is any grade 3 or 4 hematological or nonhematological toxicity, as well 
as the following:  
1. Grade 3 hyperglycemia that can be brought down to grade 1 within a week (both 


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34 
agents).   
2. Persistent refractory grade 2 rash (MK2206) despite dose withholding followed by 
reinitiation at same dose.  
3. Persistent refractory grade 2 nonhematological toxicity (everolimus) that persists 
despite dose withdholding followed by reinitiation at same dose 
4. Persistent refractory grade 2 thrombocytopenia (everolimus) that persists despite dose 
withdholding followed by reinitiation at same dose 
5. Grade 2 pneumonitis (everolimus) 
 
The following will not be considered a dose limiting toxicity 
6. Asymptomatic hyperuricemia any grade 
7. Asymptomatic lymphopenia, any grade 
 
 
Management and dose modifications associated with dose limiting toxicities are outlined in 
Section 6. 
 
5.5 
Duration of Therapy  
 
In the absence of treatment delays due to adverse events, treatment may continue until one of the 
following criteria applies: 
 
• Disease progression, 
 
• Intercurrent illness that prevents further administration of treatment, 
 
• Unacceptable adverse events(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. 
 
• Pregnancy 
 
 
5.6 
Duration of Follow Up 
 
Patients will be followed for every 3 months (by telephone, e-mail, clinic visit, or medical record 
review) after removal from study until death, whichever occurs first. Follow up of a treatment 
arm will cease once median OS has been reached for that arm.   Patients removed from study for 
unacceptable adverse events will be followed until resolution or stabilization of the adverse 
event. 
 
If a patient becomes pregnant while on trial and withdraws, the outcome of the pregnancy will be 
recorded, including the newborn if the pregnancy is carried to full term. 


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35 
 
5.7 
Criteria for Removal from Study 
 
Patients will be removed from study when any of the criteria listed in Section 5.5 applies.  The 
reason for study removal and the date the patient was removed must be documented in the Case 
Report Form. 
 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
Dose delays and dose modification for MK2206 and for everolimus are outlined in the following 
sections.  Dose withholding, dose reduction or treatment discontinuation will be performed for 
clinically important grade 3 and 4 toxicities.  Dose withholding and/or dose reduction will be 
performed for selected grade 2 toxicities summarized in Section 5.4 and outlined in detail below.  
 
6.1 
MK-2206  
 
 
Dose Level 
MK2206 Dose 
-2 
90 mg PO weekly 
-1 
135 mg PO weekly 
0 (starting dose) 
200 mg PO weekly 
 
Clinically significant Grade 3 side effects attributable to MK2206 will require dose withholding 
until grade 1 levels of toxicity are reached.  At that point drug can be restarted at the next lower 
dose level.  If after four weeks the toxicity remains completely controlled, dose re-escalation can 
be attempted at the treating physician’s discretion.   
 
If toxicity does not resolve to a grade 1 or lower levels within four weeks of drug 
discontinuation, the patient will be taken off study.   
 
Clinically significant Grade 4 side effects attributable to MK2206 which are considered 
medically relevant will result in patient being taken off study.   
 
Management of Hyperglycemia 
 
Grade 3 hyperglycemic events (>250 mg/dL) should lead to consultation with an endocrinologist 
or other specialist.  If glucose levels do no return to grade 1 or lower within one week of 
appropriate therapy, patients should be considered to have a DLT. 
Appropriate therapy will usually involve oral antihyperglycemic agents, since the inhibition of 
glucose transport into the cell by AKT/mTOR inhibitors may render insulin ineffective.  The 
goal of therapy is to keep fasting glucose <150 mg/dL, random blood glucose levels <180 
mg/dL, and Hemoglobin A1c <8%.  Glucose monitoring should be performed weekly, during the 
first cycle of therapy, and on day 1 of subsequent cycles, prior to drug administration.  
Hemoglobin A1c monitoring, for patients requiring treatment of hyperglycemia, should be 


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36 
performed with each cycle of MK-2206 therapy. 
 
Management of Rash 
 
Patients who develop grade 3 rash will have treatment withheld as outlined above.  For patients 
with persistent grade 2 rash that does not respond to conservative measures, and which in the 
opinion of the treating physician is significantly compromising quality of life, dose can be held, 
and once rash reaches grade 1 intensity or lower, MK2206 can be restarted at the same dose 
level.  If a second dose withholding is required for redevelopment of persistent refractory grade 2 
rash, dose can be withheld and then restarted at one dose level lower once rash reaches a grade 1 
or lower level.  MK2206 re-escalation can be attempted after 4 weeks if in the judgment of the 
treating physician the patient’s side effect profile warrants re-escalation.   
 
6.2 
Everolimus 
 
Table 3 Everolimus dose level modification guidelines 
Dose level Dose and schedule 
Dose Level 
Dose and schedule 
0 (starting dose) 
10 mg daily 
-1 
5 mg daily 
-2 
5mg every other day 
 
 
Table 4 Criteria for dose-modification in case of suspected toxicity and reinitiation of 
everolimus treatment 
Toxicity 
Actions 
Non-hematological toxicity 
 
Grade 2 
(pneumonitis – refer to Table 5) 
 
 
 
 
 
 
 
 
Grade 3 
(hyperlipidemia*) 
(pneumonitis – refer to Table 5) 
 
 
Grade 4  
 
 
If the toxicity is tolerable to the patient, maintain the 
same dose. If the toxicity is intolerable to patient, 
interrupt everolimus until recovery to grade ≤1. 
 
Then reintroduce everolimus at same dose. If event 
returns to grade 2, then interrupt everolimus until 
recovery to grade ≤1. Then reintroduce everolimus at 
the lower dose level. 
 
Interrupt study drug until recovery to grade ≤1. Then 
reintroduce everolimus at the lower dose level. For 
pneumonitis consider the use of a short course of 
corticosteroids. 
 
 
Discontinue everolimus. 
 
Hematological toxicity 
Grade 2 Thrombocytopenia (platelets <75, ≥ 
50x109/L) 
 
 
 
 
Interrupt study drug until recovery to grade ≤1 (>75 
x109/L). Then reintroduce study drug at initial dose. If 
thrombocytopenia again returns to grade 2, interrupt 
study drug until recovery to grade ≤1. Then 
reintroduce study drug at the lower dose level.  


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37 
 
 
Grade 3 Thrombocytopenia (platelets <50, ≥ 
25 x109/L) 
 
 
Grade 4 Thrombocytopenia (platelets < 
25x109/L) 
 
 
 
Grade 3 Neutropenia (neutrophils <1, 
≥0.5x109/L) 
 
 
 
 
 
Grade 4 Neutropenia (neutrophils < 0.5 
x109/L) 
 
 
 
 
Grade 3 febrile neutropenia (not life-
threatening) 
 
 
 
 
 
Grade 4 febrile neutropenia (life-threatening) 
 
Interrupt study drug until recovery to grade ≤1 
(platelets ≥ 75 x109/L). Then resume study drug at one 
dose level lower. If grade 3 thrombocytopenia recurs, 
discontinue study drug.  
 
 
Discontinue study drug. 
 
 
 
 
Interrupt study drug until recovery to grade ≤1 
(neutrophils ≥ 1.5 x 109/L). Then resume study drug at 
the initial dose. If ANC again returns to Grade 3, hold 
study drug until the ANC ≥ 1.5 x 109/L. Then resume 
study drug dosing at the lower dose level. Discontinue 
patient from study therapy for a third episode of grade 
3 neutropenia. 
 
Interrupt study drug until recovery to grade ≤ 1 
(neutrophils ≥ 1.5 x 109/L). Then resume study drug at 
the lower dose level. If grade 3 or grade 4 
neutropenia occurs despite this dose reduction, 
discontinue study drug. 
 
Interrupt study drug until resolution of fever and 
neutropenia to grade ≤ 1. Hold further study drug until 
the ANC ≥ 1,500/mm3 and fever has resolved. Then 
resume study drug at the lower dose level. If febrile 
neutropenia recurs, discontinue study drug. 
 
Discontinue study drug. 
Any hematological or non-hematological 
toxicity requiring interruption for ≥ 4 
weeks 
Discontinue study drug. 
 
* Grade 3 hyperlipidemia (hypercholesterolemia and/or hypertriglyceridemia) should be managed 
using medical therapies. 
 
Management of stomatitis/oral mucositis/mouth ulcers 
Stomatitis/oral mucositis/mouth ulcers due to study drug should be treated using local 
supportive care. Please note that investigators in earlier trials have described the oral 
toxicities associated with study drug as mouth ulcers, rather than mucositis or stomatitis. 
If your examination reveals mouth ulcers rather than a more general inflammation of the 
mouth, please classify the adverse event as such. Please follow the paradigm below for 
treatment of stomatitis/oral mucositis/mouth ulcers: 
 
1.  For mild toxicity (Grade 1), use conservative measures such as non-alcoholic mouth 
wash or salt water (0.9%) mouth wash several times a day until resolution. 
2.  For more severe toxicity (Grade 2 in which case patients have pain but are able to 
maintain adequate oral alimentation, or Grade 3 in which case patients cannot 
maintain adequate oral alimentation), the suggested treatments are topical analgesic 


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38 
mouth treatments (i.e., local anesthetics such as benzocaine, butyl 
aminobenzoate, tetracaine hydrochloride,menthol, or phenol) with or without 
topical corticosteroids, such as triamcinolone oral paste 0.1% (Kenalog in 
Orabase®).  
3.  Agents containing hydrogen peroxide, iodine, and thyme derivatives may tend to 
worsen mouth ulcers. It is preferable to avoid these agents. 
4.  Antifungal agents must be avoided unless a fungal infection is diagnosed. In 
particular, systemic imidazole antifungal agents (ketoconazole, fluconazole, 
itraconazole, etc.) should be avoided in all patients due to their strong inhibition of 
metabolism of study drugs, thereby leading to higher drug level exposures. Therefore, 
topical antifungal agents are preferred if an infection is diagnosed. Similarly, antiviral 
agents such as acyclovir should be avoided unless a viral infection is diagnosed. Note: 
Stomatitis/oral mucositis should be appropriately graded using the functional grading 
given on the NCI-CTC for adverse events, version 4.0. 
 
Management of hyperlipidemia and hyperglycemia  
Treatment of hyperlipidemia should take into account the pre-treatment status and dietary 
habits. Blood tests to monitor hyperlipidemia must be taken in the fasting state. Grade 2 
hypercholesterolemia (> 300 mg/dL or 7.75 mmol/L) or Grade 2 hypertriglyceridemia 
(>2.5 x ULN) should be treated with a 3-hydroxy-3-methyl-glutaryl (HMG)-CoA 
reductase inhibitor (e.g., atorvastatin, pravastatin) or appropriate lipid-lowering 
medication, in addition to diet. Patients should be monitored clinically and through serum 
biochemistry for the development of rhabdomyolysis and other adverse events as 
required in the product label/data sheets for HMG-CoA reductase inhibitors. 
 
Note: Concomitant therapy with fibrates and an HMG-CoA reductase inhibitor is 
associated with an increased risk of a rare but serious skeletal muscle toxicity manifested 
by rhabdomyolysis, markedly elevated creatine kinase (CPK) levels and myoglobinuria, 
acute renal failure and sometimes death. The risk versus benefit of using this therapy 
should be determined for individual patients based on their risk of cardiovascular 
complications of hyperlipidemia. 
 
Grade 3 hyperglycemia has been observed in patients receiving everolimus therapy. It is 
suggested that optimal glucose control should be achieved before starting a patient on 
everolimus and should be monitored during everolimus therapy. 
 
 
 
 
 
 
 
 
 
 
 


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39 
 
 
Table 5 - Management of non-infectious pneumonitis 
Worst Grade 
Pneumonitis 
Required Investigations 
Management of 
Pneumonitis  
Everolimus Dose Adjustment 
Grade 1 
CT scans with lung windows 
and pulmonary function testing 
including: spirometry, DLCO, 
and room air O2 saturation at 
rest. Repeat chest x-ray/CT 
scan every 2 Cycles until 
return to baseline. 
No specific therapy 
is required 
Administer 100% of everolimus dose. 
Grade 2 
CT scan with lung windows 
and pulmonary function testing 
including: spirometry, DLCO, 
and room air O2 saturation at 
rest. Repeat each subsequent 
Cycle until return to baseline. 
Consider bronchoscopy *  
Symptomatic only. 
Prescribe 
corticosteroids if 
cough is 
troublesome. 
Hold everolimus dose until recovery 
to ≤ Grade 1. Restart everolimus at a 
reduced dose (only if patient recovers 
to Grade 1 within 3 weeks and only if 
the patient shows evidence of clinical 
benefit from the agent) Patients will 
be withdrawn from the study if they 
fail to recover to ≤ Grade 1 within 3 
weeks. 
Grade 3 
CT scan with lung windows 
and pulmonary function testing 
including: spirometry, DLCO, 
and room air O2 saturation at 
rest.; Repeat each subsequent 
Cycle until return to baseline. 
Bronchoscopy is recommended 
* 
Prescribe 
corticosteroids if 
infective origin is 
ruled out. Taper as 
medically 
indicated. 
Hold treatment until recovery to ≤ 
Grade 1. May restart protocol 
treatment within 3 weeks at a reduced 
dose (by one level) if evidence of 
clinical benefit. Patients will be 
withdrawn from the study if they fail 
to recover to ≤ Grade 1 within 3 
weeks. 
Grade 4 
CT scan with lung windows 
and required pulmonary 
function testing includes: 
spirometry, DLCO, and room 
air O2 saturation at rest. Repeat 
each subsequent Cycle until 
return to baseline. 
Bronchoscopy is recommended 
*. 
Prescribe 
corticosteroids if 
infective origin is 
ruled out. Taper as 
medically 
indicated. 
Discontinue treatment. 
*A bronchoscopy with biopsy and/or bronchoalveolar lavage is recommended. 
 
 
 
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of AEs (Section 7.1) and the characteristics of an observed AE (Section 7.2) will 
determine whether the event requires expedited (via CTEP-AERS) reporting in addition to 
routine reporting.  
 


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40 
7.1 
Comprehensive Adverse Events and Potential Risks Lists (CAEPRs) 
  
7.1.1 CAEPR for MK-2206 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
MK-2206 (NSC 749607) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of reported and/or 
potential adverse events (AE) associated with an agent using a uniform presentation of events by body system. In 
addition to the comprehensive list, a subset, the Specific Protocol Exceptions to Expedited Reporting (SPEER), 
appears in a separate column and is identified with bold and italicized text. This subset of AEs (SPEER) is a list of 
events that are protocol specific exceptions to expedited reporting to NCI (except as noted below).  Refer to the 
'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for further clarification. 
Frequency is provided based on 245 patients. Below is the CAEPR for MK-2206. 
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 2.2, June 16, 20151 
 
 Adverse Events with Possible  
 Relationship to MK-2206 
 (CTCAE 4.0 Term) 
[n= 245] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
Anemia 
 
  
CARDIAC DISORDERS 
  
 
Sinus bradycardia 
 
 Sinus bradycardia (Gr 2) 
GASTROINTESTINAL DISORDERS 
  
 
Diarrhea 
 
 Diarrhea (Gr 3) 
 
Mucositis oral 
 
 Mucositis oral (Gr 3) 
Nausea 
 
 
 Nausea (Gr 2) 
 
Vomiting 
 
 Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
Fatigue 
 
 
 Fatigue (Gr 3) 
 
Fever 
 
 Fever (Gr 2) 
INVESTIGATIONS 
  
 
Alanine aminotransferase increased 
 
  
 
Alkaline phosphatase increased 
 
  
 
Aspartate aminotransferase increased  
  
 
Creatinine increased 
 
  
 
Electrocardiogram QT corrected 
interval prolonged 
 
 Electrocardiogram QT corrected 
interval prolonged (Gr 2) 
 
Hemoglobin increased 
 
  
 
Investigations - Other (eosinophilia)  
 Investigations - Other (eosinophilia) 
(Gr 2) 
 
Investigations - Other (insulin c-
peptide increased) 
 
  
 
Lymphocyte count decreased 
 
 Lymphocyte count decreased (Gr 4) 


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41 
 
 Adverse Events with Possible  
 Relationship to MK-2206 
 (CTCAE 4.0 Term) 
[n= 245] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
 
Neutrophil count decreased 
 
 Neutrophil count decreased (Gr 4) 
 
Platelet count decreased 
 
  
 
Weight loss 
 
  
 
White blood cell decreased 
 
 White blood cell decreased (Gr 2) 
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
 Anorexia (Gr 2) 
Hyperglycemia 
 
 
 Hyperglycemia (Gr 3) 
 
Hypocalcemia 
 
  
 
Hyponatremia 
 
  
NERVOUS SYSTEM DISORDERS 
  
 
Dysgeusia 
 
  
 
Headache 
 
 Headache (Gr 2) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Dry skin 
 
 Dry skin (Gr 2) 
 
Pruritus 
 
 Pruritus (Gr 2) 
Rash maculo-papular  
 
 Rash maculo-papular (Gr 3) 
 
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. 
 
Adverse events reported on MK-2206 trials, but for which there is insufficient evidence to suggest that there 
was a reasonable possibility that MK-2206 caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Febrile neutropenia; Hemolysis; Hemolytic uremic 
syndrome; Leukocytosis 
CARDIAC DISORDERS - Atrioventricular block complete; Left ventricular systolic dysfunction; Myocardial 
infarction; Palpitations; Ventricular arrhythmia 
EAR AND LABYRINTH DISORDERS - Vertigo 
ENDOCRINE DISORDERS - Hypothyroidism 
EYE DISORDERS - Blurred vision; Conjunctivitis; Dry eye; Extraocular muscle paresis; Eye disorders - Other 
(blepharitis); Eye disorders - Other (eye swelling); Eye disorders - Other (foreign body sensation in eyes); Eye 
disorders - Other (iritis); Eye disorders - Other (mydriasis); Eye disorders - Other (visual acuity reduced); Eye pain; 
Floaters; Keratitis; Photophobia; Retinal detachment; Uveitis 
GASTROINTESTINAL DISORDERS - Abdominal distension; Abdominal pain; Ascites; Cheilitis; Colonic 
perforation; Constipation; Dry mouth; Dyspepsia; Dysphagia; Gastritis; Gastrointestinal disorders - Other 
(oropharyngeal pain ); Lip pain; Toothache 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Edema face; Edema limbs; 
Flu like symptoms; General disorders and administration site conditions - Other (throat tightness); Injection site 
reaction; Irritability; Localized edema; Non-cardiac chest pain; Pain 
IMMUNE SYSTEM DISORDERS - Allergic reaction 
INFECTIONS AND INFESTATIONS - Infections and infestations - Other (herpetic vesicular rash [due to herpes 
zoster infection]); Infections and infestations - Other (oral herpes); Lung infection; Nail infection; Paronychia; 
Pharyngitis; Rhinitis infective; Sepsis; Sinusitis; Skin infection; Urinary tract infection 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Fall 
INVESTIGATIONS - Activated partial thromboplastin time prolonged; Blood bilirubin increased; INR increased; 
Investigations - Other (blood LDH increased); Investigations - Other (hyperinsulinemia); Lipase increased; Serum 
amylase increased; Weight gain 


NCI Protocol #:  8727 
Version Date:   June 11, 2018 
 
42 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hypercalcemia; Hyperkalemia; 
Hypermagnesemia; Hypoalbuminemia; Hypokalemia; Hypomagnesemia; Hypophosphatemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; Back pain; Bone pain; 
Generalized muscle weakness; Myalgia; Neck pain; Pain in extremity 
NERVOUS SYSTEM DISORDERS - Akathisia; Dizziness; Encephalopathy; Lethargy; Presyncope; Reversible 
posterior leukoencephalopathy syndrome; Seizure; Syncope; Tremor 
PSYCHIATRIC DISORDERS - Anxiety; Confusion; Depression; Insomnia 
RENAL AND URINARY DISORDERS - Acute kidney injury; Proteinuria; Renal and urinary disorders - Other 
(renal tubular necrosis); Renal and urinary disorders - Other (glucose urine present); Urinary incontinence; Urinary 
tract pain 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Gynecomastia; Vaginal hemorrhage; Vaginal 
perforation 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Bronchial obstruction; Cough; Dyspnea; 
Epistaxis; Hypoxia; Pneumonitis; Pulmonary edema; Respiratory failure; Sore throat 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Erythema multiforme; Erythroderma; 
Hyperhidrosis; Palmar-plantar erythrodysesthesia syndrome; Photosensitivity; Purpura; Rash acneiform; Skin and 
subcutaneous tissue disorders - Other (skin irritation); Stevens-Johnson syndrome; Urticaria 
VASCULAR DISORDERS - Hematoma; Hypertension; Hypotension; Thromboembolic event 
  
 
Note: MK-2206 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. 
 
7.1.2 CAEPR for Everolimus (RAD-001, NSC 733504) 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR)  
for 
Everolimus (RAD-001, NSC 733504) 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of reported and/or 
potential adverse events (AE) associated with an agent using a uniform presentation of events by body system. In 
addition to the comprehensive list, a subset, the Specific Protocol Exceptions to Expedited Reporting (SPEER), 
appears in a separate column and is identified with bold and italicized text. This subset of AEs (SPEER) is a list of 
events that are protocol specific exceptions to expedited reporting to NCI (except as noted below). Refer to the 
'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for further clarification. 
Frequency is provided based on 3033 patients. Below is the CAEPR for Everolimus (RAD-001). 
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 2.4, July 10, 20171 
 
 Adverse Events with Possible  
 Relationship to Everolimus (RAD-001) 
 (CTCAE 4.0 Term) 
[n= 3033] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
Anemia 
 
 
 Anemia (Gr 2) 
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
  


NCI Protocol #:  8727 
Version Date:   June 11, 2018 
 
43 
 
 Adverse Events with Possible  
 Relationship to Everolimus (RAD-001) 
 (CTCAE 4.0 Term) 
[n= 3033] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
 
Constipation 
 
  
Diarrhea2 
 
 
 Diarrhea2 (Gr 2) 
Mucositis oral3 
 
 
 Mucositis oral3 (Gr 2) 
 
Nausea 
 
 Nausea (Gr 2) 
 
Vomiting 
 
 Vomiting (Gr 2) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Edema limbs 
 
 Edema limbs (Gr 2) 
Fatigue 
 
 
 Fatigue (Gr 2) 
 
Fever 
 
 Fever (Gr 2) 
INFECTIONS AND INFESTATIONS 
  
 
Infection4 
 
 Infection4 (Gr 2) 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
 
 
Wound complication5 
  
INVESTIGATIONS 
  
 
Alanine aminotransferase 
increased 
 
 Alanine aminotransferase increased 
(Gr 2) 
 
Alkaline phosphatase increased 
 
 Alkaline phosphatase increased (Gr 
2) 
 
Aspartate aminotransferase 
increased 
 
 Aspartate aminotransferase 
increased (Gr 2) 
 
Cholesterol high 
 
 Cholesterol high (Gr 2) 
 
Creatinine increased 
 
 Creatinine increased (Gr 2) 
 
Lymphocyte count decreased 
 
 Lymphocyte count decreased (Gr 2) 
 
Neutrophil count decreased 
 
 Neutrophil count decreased (Gr 2) 
 
Platelet count decreased 
 
 Platelet count decreased (Gr 2) 
 
Weight loss 
 
  
 
White blood cell decreased 
 
 White blood cell decreased  
(Gr 2) 
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
 Anorexia (Gr 2) 
 
Hyperglycemia6 
 
 Hyperglycemia6 (Gr 2) 
 
Hypertriglyceridemia 
 
 Hypertriglyceridemia (Gr 2) 
 
Hypophosphatemia 
 
 Hypophosphatemia (Gr 2) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
  
 
Back pain 
 
  
 
Pain in extremity 
 
  
NERVOUS SYSTEM DISORDERS 
  
 
Dysgeusia 
 
  
 
Headache 
 
 Headache (Gr 2) 
RENAL AND URINARY DISORDERS 
  
 
 
Acute kidney injury 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
 Cough (Gr 2) 
 
Dyspnea 
 
 Dyspnea (Gr 2) 
 
Epistaxis 
 
 Epistaxis (Gr 2) 
 
Pneumonitis7 
 
  


NCI Protocol #:  8727 
Version Date:   June 11, 2018 
 
44 
 
 Adverse Events with Possible  
 Relationship to Everolimus (RAD-001) 
 (CTCAE 4.0 Term) 
[n= 3033] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Dry skin 
 
  
 
Pruritus 
 
  
Rash maculo-papular 
 
 
 Rash maculo-papular (Gr 2) 
 
 
Skin and subcutaneous tissue 
disorders - Other (angioedema)8 
  
 
 
 
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. 
 
2Includes diarrhea, enteritis, enterocolitis, colitis, defecation urgency, and steatorrhea. 
 
3Includes stomatitis, aphthous stomatitis, gingival pain/swelling/ulceration, glossitis, glossodynia, lip ulceration, 
mouth ulceration, tongue ulceration, and mucosal inflammation. 
 
4Infection includes all 75 infection sites under the INFECTIONS AND INFESTATIONS SOC. 
 
5Everolimus delays wound healing and increases the occurrence of wound-related complications like wound 
dehiscence, wound infection, incisional hernia, lymphocele, and seroma. 
 
6Hyperglycemia may result in either exacerbation of or development new onset diabetes mellitus. 
 
7Includes pneumonitis, interstitial lung disease, lung infiltration, pulmonary alveolar hemorrhage, pulmonary 
toxicity, alveolitis, pulmonary fibrosis, and restrictive pulmonary disease. 
 
8Patients taking concomitant ACE inhibitor therapy may be at increased risk for angioedema 
9 Includes agitation, anxiety, panic attack, aggression, abnormal behavior, and obesessive compulsive disorder. 
Adverse events reported on Everolimus (RAD-001) trials, but for which there is insufficient evidence to 
suggest that there was a reasonable possibility that Everolimus (RAD-001) caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other 
(thrombotic microangiopathy) 
CARDIAC DISORDERS - Atrial fibrillation; Cardiac disorders - Other (myocardial abnormality); Chest pain - 
cardiac; Heart failure; Left ventricular systolic dysfunction; Myocardial infarction; Sinus bradycardia; Sinus 
tachycardia; Supraventricular tachycardia 
ENDOCRINE DISORDERS - Endocrine disorders - Other (increased blood follicle stimulating hormone [FSH] 
levels); Endocrine disorders - Other (increased blood luteinizing hormone [LH] levels); Endocrine disorders - Other 
(low testosterone); Hypothyroidism 
EYE DISORDERS - Blurred vision; Conjunctivitis; Keratitis 
GASTROINTESTINAL DISORDERS - Ascites; Colitis; Dry mouth; Dyspepsia; Dysphagia; Flatulence; 
Gastroesophageal reflux disease; Gastrointestinal disorders - Other (Dieulafoy's lesion); Hemorrhoids; Intra-
abdominal hemorrhage; Oral pain; Pancreatitis; Periodontal disease; Toothache 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Edema face; Edema trunk; 
Flu like symptoms; Irritability; Non-cardiac chest pain; Pain 
HEPATOBILIARY DISORDERS - Hepatic failure; Hepatobiliary disorders - Other (hepatomegaly) 


NCI Protocol #:  8727 
Version Date:   June 11, 2018 
 
45 
IMMUNE SYSTEM DISORDERS - Allergic reaction 
INVESTIGATIONS - Activated partial thromboplastin time prolonged; Blood bilirubin increased; CPK increased; 
GGT increased; INR increased; Investigations - Other (bicarbonate decreased); Investigations - Other (increased 
lactate dehydrogenase); Investigations - Other (low density lipoprotein raised); Investigations - Other 
(thrombocythemia) 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Glucose intolerance; Hypercalcemia; 
Hyperkalemia; Hypoalbuminemia; Hypocalcemia; Hypokalemia; Hypomagnesemia; Hyponatremia; Metabolism 
and nutrition disorders - Other (high ammonia); Metabolism and nutrition disorders - Other (hyperlipidemia) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Bone pain; Chest wall pain; 
Generalized muscle weakness; Muscle weakness lower limb; Musculoskeletal and connective tissue disorder - Other 
(muscle spasms); Myalgia 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Neoplasms 
benign, malignant and unspecified (incl cysts and polyps) - Other (ovarian cysts) 
NERVOUS SYSTEM DISORDERS - Dizziness; Encephalopathy; Hydrocephalus; Lethargy; Paresthesia 
PSYCHIATRIC DISORDERS - Agitation; Anxiety8; Delirium; Depression; Insomnia; Mania 
RENAL AND URINARY DISORDERS - Hematuria; Proteinuria; Urinary frequency 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Dysmenorrhea; Genital edema; Irregular 
menstruation; Menorrhagia; Vaginal hemorrhage 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Bronchopulmonary hemorrhage; 
Pharyngolaryngeal pain; Pleural effusion; Respiratory failure; Respiratory, thoracic and mediastinal disorders - 
Other (rales); Respiratory, thoracic and mediastinal disorders - Other (rhinorrhea); Sore throat; Voice alteration 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Nail loss; Palmar-plantar erythrodysesthesia syndrome; 
Rash acneiform; Skin and subcutaneous tissue disorders - Other (angioedema)9; Skin and subcutaneous tissue 
disorders - Other (skin lesion); Skin ulceration 
VASCULAR DISORDERS - Flushing; Hypertension; Lymphedema; Phlebitis; Thromboembolic event; Vascular 
disorders - Other (acute bowel ischemia); Vascular disorders - Other (hemorrhage) 
 
Note: Everolimus (RAD-001) 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. 
 
 
7.2 
Adverse Event Characteristics  
 
• CTCAE term (AE description) and grade: The descriptions and grading scales found in the 
revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be 
utilized until March 31, 2018 for AE reporting. CTCAE version 5.0 will be utilized for AE 
reporting beginning April 1, 2018. All appropriate treatment areas should have access to a 
copy of the CTCAE version 5.0. A copy of the CTCAE version 5.0 can be downloaded from 
the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
 
• 
‘Expectedness’: AEs can be ‘Unexpected’ or ‘Expected’ (see Section 7.1 above) for 
expedited reporting purposes only.  ‘Expected’ AEs (the ASAEL) are bold and italicized in 
the CAEPR (Section 7.1.1). 
 
• 
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. 


NCI Protocol #:  8727 
Version Date:   June 11, 2018 
 
46 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
 
7.3 
Expedited Adverse Event Reporting 
 
7.3.1 Expedited AE reporting for this study must use CTEP-AERS (CTEP Adverse Event 
Reporting System), accessed via the CTEP 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 7.3.3). 
 
In the rare event when Internet connectivity is disrupted a 24-hour notification is to 
be made to NCI by telephone at: 301-897-7497, or 301-897-7402 for CIP studies. 
An electronic report MUST be submitted immediately upon re-establishment of 
internet connection. Please note that all paper CTEP-AERS forms have been 
removed from the CTEP website and will NO LONGER be accepted. 
 
7.3.2 Multi-Institutional Studies 
 
CTEP-AERS is programmed for automatic electronic distribution of reports to the 
following individuals:  Study Coordinator of the Lead Organization, Principal 
Investigator, and the local treating physician.  CTEP-AERS provides a copy feature 
for other e-mail recipients.  
 
 
7.3.3 Phase 2 and 3 Trials Expedited Reporting Guidelines – CTEP-AERS  
 
Reporting Requirements for Adverse Events that occur within 30 Days1 of the Last 
Dose of the Investigational Agent on Phase 2 and 3 Trials 
 
Phase 2 and 3 Trials 
 
 
Grade 1 
 
Grade 2 
 
Grade 2 
 
Grade 3 
 
Grade 3 
Grades 
4 & 52 
Grades 
4 & 52 
Unexpected  
and Expected 
 
Unex-
pected 
 
 
Expected 
Unexpected 
Expected 
Unex- 
pected  
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 
10 
Calendar 
Days 
10 
Calendar 
Days 
Possible 
Probable 
Definite 
Not 
Required 
10 
Calendar 
Days 
Not 
Required 
10 Calendar 
Days 
10 Calendar 
Days 
10 
Calendar 
Days 
Not 
Required 
24-Hour; 
5 Calendar 
Days 
10 
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: 
CTEP-AERS 24-hour notification followed by complete report within 5 calendar days for: 
• 
Grade 4 and Grade 5 unexpected events  


NCI Protocol #:  8727 
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47 
 
CTEP-AERS 10 calendar day report: 
• 
Grade 3 unexpected events with hospitalization or prolongation of hospitalization 
• 
Grade 5 expected events 
2 Although an CTEP-AERS 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:  A death on study require both routine and expedited reporting 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 
CTEP-AERS within 24 hours of learning of the event followed by a complete 
CTEP-AERS report within 5 calendar days of the initial 24-hour report. 
➢ “10 calendar days” - A complete CTEP-AERS 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.   
 
• Any event that results in persistent or significant 
disabilities/incapacities, congenital anomalies, or birth 
defects must be reported via CTEP-AERS 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. 
 
Death due to progressive disease should be reported as Grade 5 “Disease 
progression” in the system organ class (SOC) “General disorders and 
administration site conditions.” Evidence that the death was a manifestation 
of underlying disease (e.g., radiological changes suggesting tumor growth or 
progression: clinical deterioration associated with a disease process) should 
be submitted.  
 
Pregnancy loss Example: 
 
Pregnancy loss 
• Pregnancy loss is defined in CTCAE as “Death in utero 
• Any pregnancy loss should be reported expeditiously, as Grade 4 “Pregnancy 
loss” under the Pregnancy, puerperium and perinatal conditions SOC. 
• A pregnancy loss should NOT be reported as a Grade 5 event under 
• the Pregnancy, puerperium and perinatal conditions SOC, as currently 
CTEPAERS 
• recognizes this event as a patient death. 
 
Death neonatal Example: 
A neonatal death should be reported expeditiously as Grade 4, “Death neonatal” under the 


NCI Protocol #:  8727 
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48 
General disorders and administration SOC. 
 
7.4 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions.  AEs reported through 
CTEP-AERS must also be reported in routine study data submissions. 
 
7.5 
Secondary AML/MDS 
 
Investigators are required to report cases of secondary AML/MDS occurring on or following 
treatment on NCI-sponsored chemotherapy protocols via CTEP-AERS.  Refer to the “CTEP, 
NCI Guidelines: Adverse Event Reporting Requirements” (available at http://ctep.cancer.gov) 
for additional information about secondary AML/MDS reporting.  
 
 
8. PHARMACEUTICAL INFORMATION 
 
 
8.1 
CTEP-Supplied Investigational Agents  
 
8.1.1 MK-2206 (NSC 749607)  
 
Chemical Name or Amino Acid Sequence: 8-[4-(1-aminocyclobutyl)phenyl]-9-phenyl-
1,2,4-triazolo[3,4-ƒ]-1,6-naphthyridin-3(2H)-one mono-hydrochloride salt 
 
Other Names: N/A 
 
Classification: Akt inhibitor 
 
Molecular Formula: 
C25H22N5OCl 
 
M.W.:  443.93  
 
Approximate Solubility:  Soluble in water (7.54 mg/mL; pH = 6.) but less soluble in 
acetonitrile (1.4 mg/mL) and ethanol (2 mg/mL). Its mono-hydrochloride salt is slightly 
hygroscopic (absorbs 1.9 wt% water up to 95% relative humidity).   
 
Mode of Action:  The PI3K/AKT pathway is downstream of EGFR, HER2, IGF1R, and 
cMet, and is a suspected driver of tumor progression in most cancers.  Overexpression or 
activating mutations in TKRs, PI3K and RAS, inactivation of the tumor suppressor PTEN, 
or amplification or mutation of AKT can activate AKT protein kinase in most human 
carcinomas. It is believed that AKT inhibitors that target the pathway downstream of the 
most common mutations have broader utility and provide less resistance in the clinic.   
 
Description:  A highly selective non-ATP competitive allosteric AKT inhibitor. 
 
How Supplied:  MK-2206 tablets are supplied by Merck and distributed by the DCTD, 
NCI.  The 5 mg and 25 mg bottles contain 10 and 20 tablets, respectively.  The 200-mg 


NCI Protocol #:  8727 
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49 
bottles contain 5 tablets each.  The pharmaceutical collaborator does not have stability data 
to support repackaging MK-2206 tablets in any container other than what is provided. 
 
The white film (Opadry® 20A18273) coating consists of hydroxypropyl cellulose, 
hydroxypropyl methylcellulose and titanium dioxide.  
 
Inactive ingredients consist of microcrystalline cellulose (Avicel PH102®), calcium 
phosphate dibasic anhydrous (ATAB®), crosscarmellose sodium, and magnesium stearate.  
 
Storage:  Store intact bottles at room temperature, not to exceed 30oC. 
 
Stability:   Shelf life of MK-2206 is up to 24 months. 
 
Route(s) of Administration: Oral 
 
Method of Administration: Take MK-2206 tablets 2 hours before or after food. 
 
Potential Drug Interactions:  MK-2206 is a substrate for P-glycoprotein (P-gp) mediated 
transport. 
 
Patient Care Implications:  In acute overdose, use activated charcoal to reduce the 
absorption of MK-2206.  If additional measures are needed, consider emptying the stomach.  
Administer specific medical therapy as clinically appropriate. 
 
8.1.2 Agent Ordering  
 
NCI-supplied agents may be requested by the Principal Investigator (or their authorized 
designees) at each participating institution.  Pharmaceutical Management Branch (PMB) 
policy requires that the 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. 
 
 Active CTEP-registered investigators and investigator-designated shipping designees and 
ordering designees can submit agent requests through the PMB Online Agent Order 
Processing (OAOP) application < https://eapps-ctep.nci.nih.gov/OAOP/pages/login.jspx 
>.  Access to OAOP requires the establishment of a CTEP Identity and Access 
Management (IAM) account < https://eapps-ctep.nci.nih.gov/iam/ > and the maintenance 
of an “active” account status and a “current” password.  For questions about drug orders, 
transfers, returns, or accountability call (240) 276-6575 Monday through Friday between 


NCI Protocol #:  8727 
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50 
8:30 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: Everolimus 
 
Refer to the FDA-approved product package insert for comprehensive information. 
 
How Supplied: Everolimus is commercially available as 5 mg and 10 mg tables in blisters of 28 
tablets. Each carton contains 4 blister cards of 7 tablets each.  
 
Storage: Store everolimus tablets at 25° C (77°F); excursions permitted between 15°–30°C (59°–
86°F). Store in the original container, protect from light and moisture. 
 
Stability: Everolimus tablets are stable, when stored as indicated, until the expiration date 
identified on the package label. 
 
Route of Administration: Oral 
 
 
 
9. CORRELATIVE/SPECIAL STUDIES  
 
As described in Section 2.5, tissue microarrays (TMAs), cytokine-angiogenesis factor (CAF) 
analysis and virtual karyotyping will be performed on tissue and blood samples from patients on 
this study.   
 
The tissue microarrays will be performed at the University of Texas M. D. Anderson Cancer 
Center (UTMDACC) in the Genitourinary Center core facility.    The CAF analysis will be 
performed in collaboration with Dr. Amado Zurita and Dr. John Heymach at UTMDACC.   The 
virtual karyotyping will be perfomed at UTMDACC core facility.  
 
For details on sample collection, shipment and analysis, refer to the following appendices:   
 
Appendix G: Virtual karyotype analysis 
Appendix H:  TMA analysis 
Appendix I:  CAF analysis 
 
 


NCI Protocol #:  8727 
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51 
10. STUDY CALENDAR 
 
Baseline evaluations are to be conducted within 2 week prior to start of protocol therapy.  Scans 
and x-rays must be done ≤ 4 weeks prior to the start of therapy.  In the event that the patient's 
condition is deteriorating, laboratory evaluations should be repeated within 48 hours prior to 
initiation of the next cycle of therapy.  
 
  
Screening 
Every 4 
weeksk 
Every 8 
Weeksk 
Early Withdrawal/     
End of Study 
Informed consent 
xa 
  
  
  
Medical history 
xb 
x 
  
  
Physical exam 
xb 
x 
  
x 
Vital signs 
xb 
x 
  
x 
Performance status 
xb 
x 
  
  
Weight 
xb 
x 
  
x 
Height 
xb 
  
  
  
Concurrent meds 
xb 
x 
  
x 
CBC w/diff, plts 
xb 
x 
  
x 
Serum chemistry 
xb, e 
xe, f 
  
x 
HGB A1C 
xb 
  
  
  
Fasting Glucose, Fasting 
Lipid Panel, and 
triglycerides 
xb 
xi 
xi 
  
B-HCG 
xb, c 
  
  
  
PT/PTT 
xb 
x 
  
x 
T4, TSH 
xb 
x 
  
x 
Amylase, Lipase 
xb 
xh 
  
  
Hemoglobin A1C 
  
xg 
  
  
Urinalysis 
xb 
x 
  
x 
EKG 
xa 
xj 
x 
x 
Adverse event evaluation 
<----------------------------------------------------------------> 
Chest X-Ray 
xa 
  
x 
x 
CT Scan Chest/Abdomen 
xa 
  
x 
x 


NCI Protocol #:  8727 
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52 
MRI or CT of Brain 
xa 
  
x 
x 
Bone Scan 
xa 
  
x 
x 
Other Radiological Scans 
xa, d 
  
x 
x 
Optional 
Correlative 
Blood 
x 
x 
  
x 
Optional Archived Tissue 
Collection 
x 
  
  
  
a  Within 4 weeks of study entry 
b  Within 2 weeks of study entry 
c  Within 24 hours of study entry 
d  MRI spine should be obtained if suspicion of evolving cored or nerve root compression. A 
skeletal survey and/or a CT scan of the pelvis will be ordered as clinically indicated. 
e  Serum chemistry will include total protein, albumin, alkaline phosphatase, AST and/or ALT, 
calcium, LDH, total bilirubin, BUN, creatinine, phosphorus, uric acid, sodium, potassium, 
chloride, carbon dioxide, glucose, and magnesium.  
f  Serum glucose testing will be done every 7 days for the first cycle of treatment for those 
patients receiving MK-2206. This can be done at a local physician's office. 
g  Only for patients on MK-2206 who require anti-hyperglycemic medication. 
h  Repeated only if indicated 
i  Fasting glucose and lipid panel will be done every 4 weeks for the first 8 weeks and every 8 
weeks thereafter. 
j Course 1 Day 1 post-treatment (only for patients randomized to MK-2206). 
k Patients who are progression free after 1 year may have the following performed every 12 weeks +/- 
7days 
 
 
11. MEASUREMENT OF EFFECT 
 
 
11.1 
Antitumor Effect – Solid Tumors 
 
For the purposes of this study, patients should be re-evaluated for response every   eight weeks.  
In addition to a baseline scan, confirmatory scans should also be obtained not less than 4 weeks 
following initial documentation of objective response. 
 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) [Eur J Ca 45:228-247, 2009].   
 
Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the 
shortest diameter in the case of malignant lymph nodes are used in the RECIST criteria. 
 


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53 
11.1.1 Definitions 
 
Evaluable for toxicity:  All patients will be evaluable for toxicity from the time of their 
first treatment with MK-2206. 
 
Evaluable for objective response:  Only those patients who have measurable disease 
present at baseline, have received at least one cycle of therapy, 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 cycle 1 will also be considered 
evaluable.) 
 
 
Evaluable Non-Target Disease Response:  Patients who have lesions present at baseline 
that are evaluable but do not meet the definitions of measurable disease, have received at 
least one cycle of therapy, and have had their disease re-evaluated will be considered 
evaluable for non-target disease.  The response assessment is based on the presence, 
absence, or unequivocal progression of the lesions.  
 
 
11.1.2 Disease Parameters 
 
Measurable disease:  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter for non-nodal lesions and short axis 
for nodal lesions to be recorded) as > 20 mm by chest x-ray, as >10 mm with CT scan, or 
>10 mm with calipers by clinical exam.  All tumor measurements must be recorded in 
millimeters (or decimal fractions of centimeters). 
 
Note:  Tumor lesions that are situated in a previously irradiated area might or might not 
be considered measurable.   
 
Malignant lymph nodes:  To be considered pathologically enlarged and measurable, a 
lymph node must be >15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm).  At baseline and in follow-up, only 
the short axis will be measured and followed. 
 
Non-measurable disease:  All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥ 10 to <15 mm short 
axis), are considered non-measurable disease.  Bone lesions, leptomeningeal disease, 
ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast 
disease, and abdominal masses (not followed by CT or MRI), are considered as non-
measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor non-measurable) 
since they are, by definition, simple cysts. 
 


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54 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same patient, these are preferred for selection as target 
lesions. 
 
 
Target lesions:  All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target 
lesions and recorded and measured at baseline.  Target lesions should be selected on the 
basis of their size (lesions with the longest diameter), be representative of all involved 
organs, but in addition should be those that lend themselves to reproducible repeated 
measurements.  It may be the case that, on occasion, the largest lesion does not lend itself 
to reproducible measurement in which circumstance the next largest lesion which can be 
measured reproducibly should be selected.  A sum of the diameters (longest for non-
nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and 
reported as the baseline sum diameters.  If lymph nodes are to be included in the sum, 
then only the short axis is added into the sum.  The baseline sum diameters will be used 
as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
 
Non-target lesions:  All other lesions (or sites of disease) including any measurable 
lesions over and above the 5 target lesions should be identified as non-target lesions and 
should also be recorded at baseline.  Measurements of these lesions are not required, but 
the presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow-up.  
 
 
 
 
 
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 by chest 
x-ray or as ≥10 mm with CT scan, MRI, or calipers by clinical exam.  All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters). 
 
Note:  Tumor lesions that are situated in a previously irradiated area might or might not 
be considered measurable.  If the investigator thinks it appropriate to include them, the 
conditions under which such lesions should be considered must be defined in the 
protocol. 
 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a 
lymph node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm).  At baseline and in follow-up, only 
the short axis will be measured and followed. 
 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions 


NCI Protocol #:  8727 
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55 
(longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), 
are considered non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
and abdominal masses (not followed by CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor non-measurable) 
since they are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same patient, these are preferred for selection as target 
lesions. 
 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target 
lesions and recorded and measured at baseline.  Target lesions should be selected on the 
basis of their size (lesions with the longest diameter), be representative of all involved 
organs, but in addition should be those that lend themselves to reproducible repeated 
measurements.  It may be the case that, on occasion, the largest lesion does not lend itself 
to reproducible measurement in which circumstance the next largest lesion which can be 
measured reproducibly should be selected.  A sum of the diameters (longest for non-
nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and 
reported as the baseline sum diameters.  If lymph nodes are to be included in the sum, 
then only the short axis is added into the sum.  The baseline sum diameters will be used 
as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
 
Non-target lesions.  All other lesions (or sites of disease) including any measurable 
lesions over and above the 5 target lesions should be identified as non-target lesions and 
should also be recorded at baseline.  Measurements of these lesions are not required, but 
the presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow-up.  
 
11.1.3 Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers.  All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment. 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam. 
 


NCI Protocol #:  8727 
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56 
Clinical lesions:  Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and 10 mm diameter as 
assessed using calipers (e.g., skin nodules).  In the case of skin lesions, documentation by 
color photography, including a ruler to estimate the size of the lesion, is recommended.  
 
Chest x-ray:  Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung.  However, CT is preferable.  
 
Conventional CT and MRI:  This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm or less.  If CT scans have 
slice thickness greater than 5 mm, the minimum size for a measurable lesion should be 
twice the slice thickness.  MRI is also acceptable in certain situations (e.g. for body 
scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement.  Furthermore, the 
availability of MRI is variable globally.  As with CT, if an MRI is performed, the 
technical specifications of the scanning sequences used should be optimized for the 
evaluation of the type and site of disease.  Furthermore, as with CT, the modality used at 
follow-up should be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence.  It is beyond the scope of the RECIST 
guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases.  Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior scans.  Body scans 
should be performed with breath-hold scanning techniques, if possible. 
 
PET-CT:  At present, the low dose or attenuation correction CT portion of a combined 
PET-CT is not always of optimal diagnostic CT quality for use with RECIST 
measurements.  However, if the site can document that the CT performed as part of a 
PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), 
then the CT portion of the PET-CT can be used for RECIST measurements and can be 
used interchangeably with conventional CT in accurately measuring cancer lesions over 
time.  Note, however, that the PET portion of the CT introduces additional data which 
may bias an investigator if it is not routinely or serially performed.   
 
Ultrasound:  Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement.  Ultrasound examinations cannot be reproduced in their 
entirety for independent review at a later date and, because they are operator dependent, it 
cannot be guaranteed that the same technique and measurements will be taken from one 
assessment to the next.  If new lesions are identified by ultrasound in the course of the 
study, confirmation by CT or MRI is advised.  If there is concern about radiation 
exposure at CT, MRI may be used instead of CT in selected instances. 
 
 
Endoscopy, Laparoscopy:  The utilization of these techniques for objective tumor 


NCI Protocol #:  8727 
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57 
evaluation is not advised.  However, such techniques may be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials where 
recurrence following complete response (CR) or surgical resection is an endpoint. 
 
Tumor markers: Tumor markers alone cannot be used to assess response.  If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered 
in complete clinical response.  Specific guidelines for both CA-125 response (in recurrent 
ovarian cancer) and PSA response (in recurrent prostate cancer) have been published 
[JNCI 96:487-488, 2004; J Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 26:1148-1159, 
2008].  In addition, the Gynecologic Cancer Intergroup has developed CA-125 
progression criteria which are to be integrated with objective tumor assessment for use in 
first-line trials in ovarian cancer [JNCI 92:1534-1535, 2000]. 
 
Cytology, Histology:  These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor 
types, such as germ cell tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or 
stable disease is mandatory to differentiate between response or stable disease (an 
effusion may be a side effect of the treatment) and progressive disease. 
 
FDG-PET:  While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis 
of FDG-PET imaging can be identified according to the following algorithm:  
 
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a 
sign of PD based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the 
positive FDG-PET at follow-up corresponds to a new site of disease 
confirmed by CT, this is PD.  If the positive FDG-PET at follow-up is not 
confirmed as a new site of disease on CT, additional follow-up CT  scans 
are needed to determine if there is truly progression occurring at that site 
(if so, the date of PD will be the date of the initial abnormal FDG-PET 
scan).  If the positive FDG-PET at follow-up corresponds to a pre-existing 
site of disease on CT that is not progressing on the basis of the anatomic 
images, this is not PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar 
to a biopsy in cases where a residual radiographic abnormality is thought 
to represent fibrosis or scarring.  The use of FDG-PET in this 
circumstance should be prospectively described in the protocol and 
supported by disease-specific medical literature for the indication.  
However, it must be acknowledged that both approaches may lead to false 
positive CR due to limitations of FDG-PET and biopsy 
resolution/sensitivity. 


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58 
d. AKT inhibition inhibits cellular membrane glucose transporters, so that 
alterations in FDG uptake may demonstrate a pharmacodynamic activity 
of MK-2206, but may not correlate with antitumor activity. 
  
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image. 
 
 
11.1.4 Response Criteria 
 
11.1.4.1 
Evaluation of Target Lesions 
 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to <10 
mm. 
 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters. 
 
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study).  In addition to the relative increase of 
20%, the sum must also demonstrate an absolute increase of at least 5 mm.  (Note:  
the appearance of one or more new lesions is also considered progressions). 
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 
 
 
11.1.4.2 
Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions and normalization 
of tumor marker level.  All lymph nodes must be non-pathological in size (<10 mm 
short axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response. 
 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 
 
Progressive Disease (PD):  Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions.  Unequivocal progression 
should not normally trump target lesion status.  It must be representative of overall 


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59 
disease status change, not a single lesion increase.     
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion 
of the treating physician should prevail in such circumstances, and the progression 
status should be confirmed at a later time by the review panel (or Principal 
Investigator). 
 
11.1.4.3 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).  The patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria. 
  
For Patients with Measurable Disease (i.e., Target Disease) 
 


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60 
Target 
Lesions 
Non-
Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall 
Response when 
Confirmation is 
Required* 
CR 
CR 
No 
CR 
>4 wks. 
Confirmation** 
CR 
Non-
CR/Non-
PD 
No 
PR 
 
>4 wks. 
Confirmation** 
CR 
Not 
evaluated 
No 
PR 
PR 
Non-
CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-
CR/Non-
PD/not 
evaluated 
No 
SD 
documented at least 
once >4 wks. from 
baseline** 
PD 
Any 
Yes or 
No 
PD 
 
no prior SD, PR or CR 
Any 
PD*** 
Yes or 
No 
PD 
Any 
Any 
Yes 
PD 
*      See RECIST 1.1 manuscript for further details on what is evidence 
of a new lesion. 
**    Only for non-randomized trials with response as primary endpoint. 
***  In exceptional circumstances, unequivocal progression in non-target 
lesions may be accepted as disease progression. 
 
Note: Patients with a global deterioration of health status requiring 
discontinuation of treatment without objective evidence of disease 
progression at that time should be reported as “symptomatic 
deterioration.”  Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 


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61 
*  ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease 
since SD is increasingly used as an endpoint for assessment of efficacy in 
some trials so to assign this category when no lesions can be measured is not 
advised 
 
 
11.1.5 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first 
date that recurrent or progressive disease is objectively documented (taking as reference 
for progressive disease the smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met 
for CR until the first date that progressive disease is objectively documented. 
 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started, including the baseline measurements. 
 
11.1.6 Progression-Free Survival 
 
PFS is defined as the duration of time from randomization to time of progression or 
death, whichever occurs first. 
 
 
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).  Note:  All adverse events that have occurred on the study, 
including those reported through CTEP-AERS, must be reported via CDUS. 
 
 
12.1.2 Responsibility for Data Submission 
 
Study participants are responsible for submitting CDUS data and/or data forms to the 


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62 
Coordinating Center quarterly to allow time for Coordinating Center compilation, 
Principal Investigator review, and timely submission to CTEP (see Section 12.1.1.).   
 
The Coordinating Center is responsible for compiling and submitting CDUS data to 
CTEP for all participants and for providing the data to the Principal Investigator for 
review.  
12.2 
CTEP Multicenter Guidelines 
 
This protocol will adhere to the policies and requirements of the CTEP Multicenter Guidelines.  
The specific responsibilities of the Principal Investigator and the Coordinating Center (Study 
Coordinator) and the procedures for auditing are presented in Appendix B. 
 
• The Principal Investigator/Coordinating Center is responsible for distributing all IND Action 
Letters or Safety Reports received from CTEP to all participating institutions for submission 
to their individual IRBs for action as required. 
 
• Except in very unusual circumstances, each participating institution will order DCTD-
supplied agents directly from CTEP.  Agents may be ordered by a participating site only after 
the initial IRB approval for the site has been forwarded by the Coordinating Center to the 
CTEP PIO (PIO@ctep.nci.nih.gov) except for Group studies. 
 
 
12.3 
Collaborative Agreements Language 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, Agent-CRADA, CTA, CSA) between the 
Pharmaceutical Company(ies) (hereinafter referred to as a “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 


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63 
access to and use of data by each Collaborator shall be as follows (data pertaining to such 
combination use shall hereinafter be referred to as “Multi-Party Data”): 
 
a. NCI will provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with 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 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: 
 


NCI Protocol #:  8727 
Version Date:   June 11, 2018 
 
64 
Regulatory Affairs Branch, CTEP, DCTD, NCI 
Executive Plaza North, Suite 7111 
Bethesda, Maryland  20892 
FAX 301-402-1584 
Email: ncicteppubs@mail.nih.gov 
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 
proprietary information. 
 
 
13. STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design/Endpoints 
 
 This is an open-label, multi-center, randomized phase II study. Patients will be randomized 
using 2:1 ratio to receive either MK2206 or everolimus. The primary endpoint of the study is 
progression-free survival (PFS), where an event is defined as either disease progression or death. 
The anticipated median PFS is 4.9 months and 8.2 months for the everolimus and MK2206 arms, 
respectively. The secondary endpoints include safety, overall survival (OS), overall response rate 
(ORR) and time to failure (TTF). For the primary endpoint, one interim futility analysis will be 
performed when a total of 38 events have occurred.  The O’Brien-Fleming stopping boundaries 
using Lan-DeMets spending function will be used for early rejection of H1 (futility boundaries). 
At the interim look, if the nominal critical point (Z-scale) is less than 0.051, we will terminate 
trial, reject H1, and conclude that MK2206 has no significant effect on improving PFS.  
Assuming that the alternative hypothesis holds and trial is continued to completion without 
interim analysis, 105 patients with 75 events provide 81% power to reject null hypothesis.  Since 
this trial has one interim analysis, 105 patients with 75 events provide 80% power to reject null 
hypothesis. Please see the detail information for power calculation in section 13.2 sample size / 
power calculation.  
 
Additionally, toxicity will be monitored for the MK2206 arm. For the purpose of implementing 
this safety rule, toxicity will be defined as Grade 3 or greater toxicity that requires treatment 
discontinuation. The method of Thall, Simon and Estey (1995, 1996) will be used. Denoting the 
probability of toxicity by p, the trial will be stopped early if for the MK2206 arm, Prob(p > 
0.30|data ) > .93. That is, if at any time during the trial, we determine that there is more than 93% 
chance that the toxicity rate for the MK2206 arm is greater than 30%, we will stop the trial. 
Assuming a beta(0.6, .1.4) priori for p, the above decision criterion implies that we will stop the 
trial if  [# patients with toxicities in the MK2206 arm]/ [# patients evaluated in the MK2206 arm] 
>/= 3/4,  4/5, 5/7, 6/9, 7/12, 8/14, 9/17, 10/20, 11/22, 12/25, 13/28, 14/30, 15/33, 16/36, 17/39, 
18/42, 19/44, 20/47, 21/50, 22/53, 23/56, 24/59, 25/62, 26/65, 27/68. The operating 
characteristics for this toxicity monitoring rule are illustrated in Table 6. 
 
Table 6. Operating Characteristics for Toxicity Monitoring Rule.  
True toxicity rate 
Prob (stop the trial early) 
Sample Size 
25th, 50th and 75th percentiles 


NCI Protocol #:  8727 
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65 
0.10 
0.005 
70, 70, 70 
0.20 
0.047 
70, 70, 70 
0.30 
0.288 
41, 70, 70 
0.40 
0.784 
8, 24, 61 
0.50 
0.990 
4, 10, 19 
 
This study will be monitored by the MDACC DSMB. 
 
13.2 
Sample Size/ Power Calculation 
 
Assuming that the median progression-free survival (PFS) is 4.9 months and 8.2 months for the 
everolimus and MK2206 arm, respectively and patients will be randomized with 2:1 ratio into 
the MK2206 arm and the everolimus arm, then with a total of 75 events (i.e., disease progression 
or death), we will have an 80% power to detect such a 67% increase in median PFS using one-
sided log-rank test and at a 0.10 significance level. The total number of patients to be enrolled 
will be 105, with 35 on the everolimus arm and 70 on the MK2206 arm. The above calculation 
also assumes an accrual rate of 4 patients per month, thus it will take 26.3 months to accrue all 
105 patients. The maximum study duration will be around 29 months, which include patients’ 
accrual period and a follow-up period. East5 software was used for the sample size/power 
calculation. 
 
13.3 
Stratification Factors 
 
Patients will be stratified by the MSKCC criteria (Appendix J) and type of prior therapy before 
being randomized into the MK2206 arm and the everolimus arm using a ratio of 2:1. The 
stratified randomization will be conducted through the Clinical Trial Conduct (CTC) website 
(https://biostatistics.mdanderson.org/ClinicalTrialConduct) maintained by the Department of 
Biostatistics of the University of Texas, M. D. Anderson Cancer Center. 
 
13.4 
Statistical Analysis Plan 
 
The primary endpoint, progression-free survival (PFS), is defined as the time interval between 
date of treatment and date of disease progression, date of death or last follow-up date, whichever 
occurred first. The probability of PFS be estimated using the Kaplan-Meier method and will be 
compared between the two treatment arms using stratified log-rank test.  Patients’ safety data 
will be summarized by treatment arm, category, severity and relevance.  
 
For secondary analyses, the Kaplan-Meier method will be used to estimate overall survival (OS) 
and time to failure (TTF), and stratified log-rank test will be used to compare between the two 
treatment arms. The OS is defined as the time interval between the date of treatment and the date 
of death or last follow-up, whichever occurred first. The TTF is defined as the time interval 
between the date of treatment and the date of disease progression, date of death, date of treatment 
discontinuation due to severe toxicity or last follow-up date, whichever occurred first. Overall 
response (OR) is defined as CR+PR and logistic regression model will be fit to assess the effect 
of treatment on the rate of OR.  
 
Since the correlative studies being performed are by nature exploratory, and have not been 


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66 
performed before in patients with RCC receiving mTOR inhibitors or AKT inhibitors, powering 
of these endpoints is not possible.  Clinical benefit is defined as CR+PR+SD and again, we will 
fit logistic regression models to assess the effects of treatment, AKT activation, circulating 
cytokines and angiogenic factors, and karyotype on clinical benefit. The interaction effect 
between treatment and these exploratory factors will also be evaluated. 
 
For virtual karyotyping, technique specific statistical analyses are outlined in Appendix G. 
 
 
 
13.5 
Reporting and Exclusions 
 
13.5.1 Evaluation of Toxicity 
 
All patients will be evaluable for toxicity from the time of their first treatment with MK-
2206. 
 
13.5.2 Evaluation of Response 
 
All patients included in the study must be assessed for response to treatment, even if there 
are major protocol treatment deviations or if they are ineligible.  Each patient will be 
assigned one of the following categories:  1) complete response, 2) partial response, 3) 
stable disease, 4) progressive disease, 5) early death from malignant disease, 6) early 
death from toxicity, 7) early death because of other cause, or 9) unknown (not assessable, 
insufficient data).  [Note:  By arbitrary convention, category 9 usually designates the 
“unknown” status of any type of data in a clinical database.] 
 
All of the patients who met the eligibility criteria (with the possible exception of those 
who received no study medication) should be included in the main analysis of the 
response rate.  Patients in response categories 4-9 should be considered to have a 
treatment failure (disease progression).  Thus, an incorrect treatment schedule or drug 
administration does not result in exclusion from the analysis of the response rate.  Precise 
definitions for categories 4-9 will be protocol specific.  
 
All conclusions should be based on all eligible patients.  Subanalyses may then be 
performed on the basis of a subset of patients, excluding those for whom major protocol 
deviations have been identified (e.g., early death due to other reasons, early 
discontinuation of treatment, major protocol violations, etc.).  However, these 
subanalyses may not serve as the basis for drawing conclusions concerning treatment 
efficacy, and the reasons for excluding patients from the analysis should be clearly 
reported.  The 95% confidence intervals should also be provided. 
 


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67 
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2 Cejka, D., M. Preusser, A. Woehrer, et al.  (2008).  Everolimus (RAD001) and anti-
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4 Fry, M.J.  (2001).  Phosphoinositide 3-kinase signalling in breast cancer: how big a role 
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5 Han, Z., K. Wu, H. Shen, et al.  (2008).  Akt1/protein Kinase Bα is Involved in Gastric 
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6 Hennessy, B.T., D.L. Smith, P.T. Ram, et al.  (2005).  Exploiting the PI3K/AKT pathway for 
cancer drug discovery.  Nat Rev Drug Discov.  4:988-1004. 
 
7 Hu, L., J. Hofmann, Y. Lu, et al.  (2002).  Inhibition of phosphatidylinositol 3'-kinase 
increases efficacy of paclitaxel in in vitro and in vivo ovarian cancer models.  Cancer Res.  
62:1087-1092. 
 
8 Investigator's Brochure.  (2008).  MK-2206.  Merck & Co, Inc.   
 
9 Kawauchi, K., T. Ogasawara, M. Yasuyama, et al.  (2009).  The PI3K/Akt pathway as a 
target in the treatment of hematologic malignancies.  Anti-cancer Ag Medicin Chem.  9:550. 
 
10 Kinkade, C.W., M. Castillo-Martin, A. Puzio-Kuter, et al.  (2008).  Targeting AKT/mTOR 
and ERK MAPK signaling inhibits hormone-refractory prostate cancer in a preclinical mouse 
model.  J Clin Invest.  118:3051. 
 
11 Kirkegaard, T., C.J. Witton, L.M. McGlynn, et al.  (2005).  AKT activation predicts outcome 
in breast cancer patients treated with tamoxifen.  J Pathol.  207:139-146. 
 
12 Konecny, G.E., M.D. Pegram, N. Venkatesan, et al.  (2006).  Activity of the Dual Kinase 
Inhibitor Lapatinib (GW572016) against HER-2-Overexpressing and Trastuzumab-Treated 
Breast Cancer Cells.  Cancer Res.  66:1630-1639. 
 
13 Kornblau, S.M., M. Womble, Y.H. Qiu, et al.  (2006).  Simultaneous activation of multiple 
signal transduction pathways confers poor prognosis in acute myelogenous leukemia.  Blood.  
108:2358-2365. 
 


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68 
14 Lee, J.W., Y.H. Soung, S.Y. Kim, et al.  (2004).  PIK3CA gene is frequently mutated in 
breast carcinomas and hepatocellular carcinomas.  Oncogene.  24:1477-1480. 
 
15 Min, Y.H., J.I. Eom, J.W. Cheong, et al.  (2003).  Constitutive phosphorylation of Akt//PKB 
protein in acute myeloid leukemia: its significance as a prognostic variable.  Leukemia.  
17:995-997. 
 
16 Nakanishi, K., M. Sakamoto, S. Yamasaki, et al.  (2005).  Akt phosphorylation is a risk 
factor for early disease recurrence and poor prognosis in hepatocellular carcinoma.  Cancer.  
103:307-312. 
 
17 Nakayama, K., N. Nakayama, R.J. Kurman, et al.  (2006).  Sequence mutations and 
amplification of PIK3CA and AKT2 genes in purified ovarian serous neoplasms.  Cancer 
Biol Ther.  5:779-785. 
 
18 Oki, E., B. Baba, E. Tokunaga, et al.  (2005).  Akt phosphorylation associates with LOH of 
PTEN and leads to chemoresistance for gastric cancer.  Int J Cancer.  117:376-380. 
 
19 Oza, A.M.  (2006).  Molecular correlates associated with a phase II study of temsirolimus 
(CCI-779) in patients with metastatic or recurrent endometrial cancer–NCIC IND 160.  J 
Clin Oncol.  24:A3003. 
 
20 Rahman, M.A., D.K. Ioannis, O. Takashi, et al.  (2002).  Impact of PTEN expression on the 
outcome of hepatitis C virus-positive cirrhotic hepatocellular carcinoma patients: Possible 
relationship with COX II and inducible nitric oxide synthase.  Int J Cancer.  100:152-157. 
 
21 Saal, L.H., K. Holm, M. Maurer, et al.  (2005).  PIK3CA mutations correlate with hormone 
receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in 
human breast carcinoma.  Cancer Res.  65:2554-2559. 
 
22 Salvesen, H.B., S.L. Carter, M. Mannelqvist, et al.  (2009).  Integrated genomic profiling of 
endometrial carcinoma associates aggressive tumors with indicators of PI3 kinase activation.  
PNAS.  106:4834-4839. 
 
23 Shayesteh, L., Y. Lu, W.L. Kuo, et al.  (1999).  PIK3CA is implicated as an oncogene in 
ovarian cancer.  Nat Genet.  21:99-102. 
 
24 Shoman, N., S. Klassen, A. McFadden, et al.  (2005).  Reduced PTEN expression predicts 
relapse in patients with breast carcinoma treated by tamoxifen.  Mod Pathol.  18:250-259. 
 
25 Sosman, J.A., I. Puzanov, and M.B. Atkins.  (2007).  Opportunities and Obstacles to 
Combination Targeted Therapy in Renal Cell Cancer.  Clin Cancer Res.  13:764s-769. 
 
26 St-Germain, M.-E., V. Gagnon, S. Parent, and E. Asselin.  (2004).  Regulation of COX-2 
protein expression by Akt in endometrial cancer cells is mediated through NF-
kappaB/IkappaB pathway.  Mol Cancer.  3:7. 


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27 Staal, S.P.  (1987).  Molecular cloning of the akt oncogene and its human homologues AKT1 
and AKT2: amplification of AKT1 in a primary human gastric adenocarcinoma.  PNAS.  
84:5034-5037. 
 
28 Steelman, L.S., K.M. Stadelman, W.H. Chappell, et al.  (2008).  Akt as a therapeutic target in 
cancer.  Exp Opin Ther Targ.  12:1139-1165. 
 
29 Tanno, S., S. Tanno, Y. Mitsuuchi, et al.  (2001).  AKT activation up-regulates insulin-like 
growth factor I receptor expression and promotes invasiveness of human pancreatic cancer 
cells.  Cancer Res.  61:589-593. 
 
30 Testa, J.R., and A. Bellacosa.  (2001).  AKT plays a central role in tumorigenesis.  PNAS.  
98:10983-10985. 
 
31 Uddin, S., A.R. Hussain, A.K. Siraj, et al.  (2006).  Role of phosphatidylinositol 3'-
kinase/AKT pathway in diffuse large B-cell lymphoma survival.  Blood.  108:4178-4186. 
 
32 Vestey, S.B., C. Sen, C.J. Calder, et al.  (2005).  Activated Akt expression in breast cancer: 
correlation with p53, Hdm2 and patient outcome.  Eur J Cancer.  41:1017-1025. 
 
33 Wolf, J., and B.M. Slomovitz.  (2005).  Novel biologic therapies for the treatment of 
endometrial cancer.  Int J Gyn Cancer.  15:411-411 
 
 
34 Thall, PF, Simon, R, Estey, EH: Bayesian sequential monitoring designs for single-arm 
clinical trials with multiple outcomes. Statistics in Medicine 14:357-379, 1995.  
 
35 Thall, PF, Simon, R, Estey, EH: New statistical strategy for monitoring safety and efficacy in 
single-arm clinical trials. J. Clinical Oncology 14:296-303, 1996. 
 
 


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70 
APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
 
ECOG Performance Status Scale 
 
Grade 
Descriptions 
0 
Normal activity.  Fully active, able to carry on all pre-disease 
performance without restriction. 
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). 
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. 
3 
In bed >50% of the time.  Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-
care.  Totally confined to bed or chair. 
5 
Dead. 
 
 
 
 
 
 
 
 
 


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71 
APPENDIX B 
CTEP MULTICENTER GUIDELINES 
 
If an institution wishes to collaborate with other participating institutions in performing a CTEP 
sponsored research protocol, then the following guidelines must be followed. 
 
Responsibility of the Protocol Chair  
• The Protocol Chair will be the single liaison with the CTEP Protocol and Information 
Office (PIO).  The Protocol Chair is responsible for the coordination, development, 
submission, and approval of the protocol as well as its subsequent amendments.  The 
protocol must not be rewritten or modified by anyone other than the Protocol Chair.  
There will be only one version of the protocol, and each participating institution will use 
that document.  The Protocol Chair is responsible for assuring that all participating 
institutions are using the correct version of the protocol. 
• The Protocol Chair is responsible for the overall conduct of the study at all participating 
institutions and for monitoring its progress.  All reporting requirements to CTEP are the 
responsibility of the Protocol Chair.  
• The Protocol Chair is responsible for the timely review of Adverse Events (AE) to assure 
safety of the patients. 
• The Protocol Chair will be responsible for the review of and timely submission of data 
for study analysis. 
 
Responsibilities of the Coordinating Center 
• Each participating institution will have an appropriate assurance on file with the Office 
for Human Research Protection (OHRP), NIH.  The Coordinating Center is responsible 
for assuring that each participating institution has an OHRP assurance and must maintain 
copies of IRB approvals from each participating site.  
•  Prior to the activation of the protocol at each participating institution, an OHRP form 
310 (documentation of IRB approval) must be submitted to the CTEP PIO. 
• The Coordinating Center is responsible for central patient registration.  The Coordinating 
Center is responsible for assuring that IRB approval has been obtained at each 
participating site prior to the first patient registration from that site. 
• The Coordinating Center is responsible for the preparation of all submitted data for 
review by the Protocol Chair. 
• The Coordinating Center will maintain documentation of AE reports.  There are two 
options for AE reporting: (1) participating institutions may report directly to CTEP with a 
copy to the Coordinating Center, or (2) participating institutions report to the 
Coordinating Center who in turn report to CTEP.  The Coordinating Center will submit 
AE reports to the Protocol Chair for timely review. 
• Audits may be accomplished in one of two ways:  (1) source documents and research 
records for selected patients are brought from participating sites to the Coordinating 
Center for audit, or (2) selected patient records may be audited on-site at participating 
sites.  If the NCI chooses to have an audit at the Coordinating Center, then the 
Coordinating Center is responsible for having all source documents, research records, all 
IRB approval documents, NCI Drug Accountability Record forms, patient registration 
lists, response assessments scans, x-rays, etc. available for the audit. 


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72 
 
Inclusion of Multicenter Guidelines in the Protocol 
• The protocol must include the following minimum information:  
➢ The title page must include the name and address of each participating institution and 
the name, telephone number and e-mail address of the responsible investigator at each 
participating institution. 
➢ The Coordinating Center must be designated on the title page. 
➢ Central registration of patients is required.  The procedures for registration must be 
stated in the protocol. 
➢ Data collection forms should be of a common format.  Sample forms should be 
submitted with the protocol.  The frequency and timing of data submission forms to 
the Coordinating Center should be stated. 
➢ Describe how AEs will be reported from the participating institutions, either directly 
to CTEP or through the Coordinating Center. 
➢ Describe how Safety Reports and Action Letters from CTEP will be distributed to 
participating institutions.  
 
Agent Ordering 
• Except in very unusual circumstances, each participating institution will order DCTD-
supplied investigational agents directly from CTEP.  Investigational agents may be 
ordered by a participating site only after the initial IRB approval for the site has been 
forwarded by the Coordinating Center to the CTEP PIO.  
 
 
 
 
 


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73 
APPENDIX C 
LIST OF CYP3A4 INHIBITORS AND INDUCERS 
 
CYP3A4 Inhibitors 
Acetominophen 
Acetazolamide 
Amiodarone 
Amlodipine 
Amprenavir 
Anastrozole 
Aprepitant 
Atazanavir 
Atorvastatin 
Azelastine 
Azithromycin 
Betamethasone 
Bortezomib 
Bromocriptine 
Caffeine 
Cerivastatin 
Chloramphenicol 
Chlorzoxazone 
Cimetidine 
Ciprofloxacin 
Cisapride 
Clarithromycin 
Clemastine 
Clofazimine 
Clotrimazole 
Clozapine 
Cocaine 
Conivaptan 
Cyclophosphamide 
Cyclosporine 
Danazol 
Dasatinib (1) 
Delavirdine 
Desipramine 
Dexmedetomidine 
Diazepam 
Diclofenac 
Dihydroergotamine 
Diltiazem 
Disulfiram 
Docetaxel 
Doxorubicin 
Doxycycline 
Drospirenone 
Efavirenz 
Enoxacin 
Entacapone 
Ergotamine 
Erythromycin 
Ethinyl estradiol 
Etoposide 
Felodipine 
Fentanyl 
Fluconazole 
Fluoxetine 
Fluvastatin 
Fluvoxamine 
Fosamprenavir 
Glyburide 
Grapefruit juice (2) 
Haloperidol 
Hydralazine 
Ifosfamide 
Imatinib 
Indinavir 
Irbesartan 
Isoniazid 
Isradipine 
Itraconazole 
Ketoconazole 
Lansoprazole 
Lidocaine 
Lomustine 
Losartan  
Lovastatin 
Mefloquine 
Mestranol 
Methadone 
Methimazole 
Methoxsalen 
Methylprednisolone 
Metronidazole 
Miconazole 
Midazolam 
Mifepristone 
Mirtazapine 
Mitoxantrone 
Modafinil 
Nefazodone 
Nelfinavir 
Nevirapine 
Nicardipine 
Nifedipine 
Nisoldipine 
Nizatidine 
Norfloxacin 
Olanzapine 
Omeprazole 
Orphenadrine 
Oxybutynin 
Paroxetine 
Pentamidine 
Pergolide 
Phencyclidine 
Pilocarpine 
Pimozide 
Pravastatin 
Prednisolone 
Primaquine 
Progesterone 
Propofol  
Propoxyphene 
Quinidine 
Quinine 
Quinupristin 
Rabeprazole 
Ranolazine 
Risperidone 
Ritonavir 
Saquinavir 
Selegiline 
Sertraline 
Sildenafil 
Sirolimus 
Sulconazole 
Tacrolimus 
Tamoxifen 
Telithromycin 
Teniposide 
Testosterone 
Tetracycline 
Ticlopidine 
Tranylcypromine 
Trazodone 
Troleandomycin 
Valproic acid 
Venlafaxine 
Verapamil 
Vinblastine 
Vincristine 
Vinorelbine 
Voriconazole 
Zafirlukast 
Ziprasidone 
 
CYP3A4 Inducers 
Aminoglutethimide 
Carbamazepine 
Fosphenytoin 
Nafcillin  
Nevirapine 
Oxcarbazepine 
Pentobarbital 
Phenobarbital  
Phenytoin 
Primidone 
Rifabutin 
Rifampin  
Rifapentine 
St. John’s wort (3) 
 
When MK-2206 is co-administered with compounds classified as ‘inhibitors’, increased plasma concentrations of MK-2206 is the potential 
outcome. The co-administration of ‘inducers’ would potentially lower plasma MK-2206 concentrations. 
 
Everolimus is a substrate of CYP3A4 and a substrate and inhibitor of P-glycoprotein. Everolimus metabolism may be affected by drugs that are 
substrates or strong inhibitors or inducers of CYP3A4 or P-glycoprotein. 
 
Note: Adapted from Cytochrome P450 Enzymes: Substrates, Inhibitors, and Inducers. In: Lacy CF, Armstrong LL, Goldman MP, Lance LL eds. 
Drug Information Handbook 15TH ed. Hudson, OH; LexiComp Inc. 2007: 1899-1912.   
Only major substrates and effective inducers are listed. 
   
Additional information for drug interactions with cytochrome P450 isoenzymes can be found at http://medicine.iupui.edu/flockhart/. 
 
(1)   Investigator’s Brochure: MK-2206. Merck. January 2009. 
 
(2)  Malhotra et al. (2001). Clin Pharmacol Ther. 69:14-23. 
 
(3)  Mathijssen et al. (2002). J Natl Cancer Inst. 94:1247-1249. 
      Frye et al. (2004). Clin Pharmacol Ther. 76:323-329. 
 
Updated on May 1, 2007 


NCI Protocol #:  8727 
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74 
 
APPENDIX D 
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.  
MK-2206 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 


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75 
Lithium 
24 hour (10-50) 
 
7 
 
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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APPENDIX E 
PATIENT’S MEDICATION DIARY 
 
 
 
 
Today’s date _____________________ 
Agent:  MK-2206 
Patient Name_____________________(initials acceptable)  
 Patient Study ID 
__________________________ 
INSTRUCTIONS TO THE PATIENT: 
1. 
Complete one form for each cycle of treatment. 
2. 
You will take MK-2206 tablets via mouth once weekly.  You should take the tablets 2 hours before or after a meal 
 
Dose:  take ___ mg tablets, ___ mg tablets, and ___  mg tablets. 
3. 
Record the date, the number of tablets of each size of tablet that 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.   
5. 
Please bring this form and your bottles of MK-2206 tablets when you return for each appointment. 
 
Day 
 
Date 
 
Time of dose  
# of tablets taken 
Comments 
 mg 
 mg 
 mg 
 
1 
 
 
 
 
 
 
2 
 
 
 
 
 
 
3 
 
 
 
 
 
 
4 
 
 
 
 
 
 
5 
 
 
 
 
 
 
6 
 
 
 
 
 
 
7 
 
 
 
 
 
 
8 
 
 
 
 
 
 
9 
 
 
 
 
 
 
10 
 
 
 
 
 
 
11 
 
 
 
 
 
 
12 
 
 
 
 
 
 
13 
 
 
 
 
 
 
14 
 
 
 
 
 
 
15 
 
 
 
 
 
 
16 
 
 
 
 
 
 
17 
 
 
 
 
 
 
18 
 
 
 
 
 
 
19 
 
 
 
 
 
 
20 
 
 
 
 
 
 
21 
 
 
 
 
 
 
22 
 
 
 
 
 
 
23 
 
 
 
 
 
 
24 
 
 
 
 
 
 
25 
 
 
 
 
 
 
26 
 
 
 
 
 
 
27 
 
 
 
 
 
 
28 
 
 
 
 
 
 
Patient’s signature  _______________________________________________________________ 
 
Physician’s Office will complete this section: 
1. 
Date patient started protocol treatment 
 
2. 
Date patient was removed from study 
 
3. 
Patient’s planned total daily dose  
4. 
Total number of tablets taken this month  
 
5. 
Physician/Nurse/Data Manager’s Signature  
 
 
CTEP-assigned Protocol #___________ 
 
Local Protocol # ___________________ 


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APPENDIX F 
PATIENT’S MEDICATION DIARY 
 
 
 
 
Today’s date _____________________ 
Agent:  Everolimus 
Patient Name_____________________(initials acceptable)  
 Patient Study ID 
__________________________ 
INSTRUCTIONS TO THE PATIENT: 
1. 
Complete one form for each cycle of treatment. 
2. 
You will take Everolimus 10 mg every day at the same time with or without food. 
 
Dose:  take 2 (5 mg tablets) or 1 (10mg tablet) 
3. 
Record the date, the number of tablets of each size of tablet that 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.   
5. 
Please bring this form and your bottles of MK-2206 tablets when you return for each appointment. 
 
Day 
 
Date 
 
Time of dose  
# of 
tablets 
taken 
Comments 
5 or 10 mg 
 
1 
 
 
 
 
2 
 
 
 
 
3 
 
 
 
 
4 
 
 
 
 
5 
 
 
 
 
6 
 
 
 
 
7 
 
 
 
 
8 
 
 
 
 
9 
 
 
 
 
10 
 
 
 
 
11 
 
 
 
 
12 
 
 
 
 
13 
 
 
 
 
14 
 
 
 
 
15 
 
 
 
 
16 
 
 
 
 
17 
 
 
 
 
18 
 
 
 
 
19 
 
 
 
 
20 
 
 
 
 
21 
 
 
 
 
22 
 
 
 
 
23 
 
 
 
 
24 
 
 
 
 
25 
 
 
 
 
26 
 
 
 
 
27 
 
 
 
 
28 
 
 
 
 
Patient’s signature  _______________________________________________________________ 
 
Physician’s Office will complete this section: 
1. 
Date patient started protocol treatment 
 
2. 
Date patient was removed from study 
 
3. 
Patient’s planned total daily dose 
 
 
CTEP-assigned Protocol #___________ 
 
Local Protocol # ___________________ 


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4. 
Total number of tablets taken this month  
 
5. 
Physician/Nurse/Data Manager’s Signature   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX G 
SNP ANALYSIS  
 
1.  Collection of Specimen(s)   
 
If patient consents to optional procedure(s), at least 2 and as many as 5 formalin fixed 
paraffin embedded blocks from nephrectomy will be acquired from each patient participating 
in the study.  These blocks will be used for TMA analysis and for virtual karyotyping.  A 
detailed laboratory manual will be provided.     
 
2.  Handling of Specimens(s) 
 
Specimens need to be kept at ambient temperatures, and reasonable efforts should be 
undertaken to avoid exposure to temperature extremes.  If necessary, samples may be 
shipped on gel packs to avoid extreme temperatures. 
 
3.  Shipping of Specimen(s) 
Samples will be batch shipped to the University of Texas M. D. Anderson Cancer Center.  
All samples will be transported according to applicable IATA regulations.   
 
Samples will be shipped to: 
 
Sherie Hodges 
University of Texas M. D. Anderson Cancer Center 
1220 Holcombe Blvd, Room ACB7.2408 
Houston, TX 77030 
Tel 713-563-3173 
Fax 713-563-0572 
GuClinicalResearchLab@mdanderson.org 
 
Once received, samples will be distributed to UTMDACC core facility for analysis. 
 
4.  Site(s) Performing Correlative Study 
 
The analysis will be performed at UTMDACC core facility.   
 
5.  Methods in brief:  An area with at least 80% tumor content will be marked on the H&E 
slide from paraffin embedded patient tissue, and this area will be manually microdissected 
from unstained slides. DNA extractions from the microdissected tissue will be performed 
with the Qiagen DNA Easy Kit (Qiagen, Valencia, CA) with modifications for FFPE tissue. 
DNA will be analyzed for chromosome copy number (CCN) changes and loss of 
heterozygosity (LOH) with the Affymetrix 250K Nsp SNP Genotyping arrays 
(Affy250KNsp) following a modified protocol.  
 
 
Data acquired from the Affymetrix GeneChip Operating System v4.0 (GCOS) will be 
analyzed using Affymetrix’s Genotyping Console v2.1.  The quality control parameters for 
each sample will be signal detection rate (the percentage of features in the array that show 
adequate fluorescence intensity) and the SNP call rate (rate of successful allele 
identification). LOH and copy number estimates will be obtained using a publicly available 
analysis package: Copy Number Analyzer for Affymetrix GeneChip arrays (CNAG v3.3). 


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Chromosomal gains and losses will be determined by the copy number estimates assigned by 
the hidden Markov model (HMM) in CNAG. LOH will be determined based on the LOH 
likelihood score as determined with CNAG with a threshold likelihood of 12. Extent and 
boundaries of the chromosomal lesions will be recorded for each lesion in all tumor samples.  
 
6.  Statistical Analysis:  Univariate and multivariate Cox proportional hazards regression will 
be performed to model the effects of various chromosomal abnormalities, nuclear grade, 
pathologic stage, and clinical outcome (PFS, OS).   Kaplan-Meier analysis and Cox 
regression will be performed using Stata 10 (College Station, TX).   
 
 
Classification analysis will also be performed to identify profiles of chromosomal 
abnormalities that predict progression and death.  Chromosomal abnormalities that are 
informative for classification will be identified by filtering with a Mahalanobis distance-
based greedy plus-take-away-1 heuristic based on a sequential forward-backward stepwise 
procedure. Performance and area under the curve (AUC) will be compared by using k nearest 
neighbor, naive Bayes, linear/quadratic/Fisher's discriminant analysis, random forests, linear 
vector quantization, kernel regression, support vector machines, particle swarm optimization, 
and artificial neural networks.  Random forests will be applied to pre-selected features, so the 
results will essentially represent the 0.632 bootstrap method. 
 
 
 
For sample size determination, using PASS 2008 (Kaysville, UT) and a one-sided logrank 
test, for a sample size of N=60 (N=30 in the response group and N=30 in the non-response 
group), a median PFS of 3.5 months for non-response and 7.5 months for response, the 
hazard ratio is 2.14 and the power to reject the null hypothesis (one-sided alternative) that 
response PFS is equal to or more than median non-response PFS is 86.5%.  Based on the 
patients proposed for this study and survival projections, we should be able to attain 
statistical power > 90%. 
 
7. Method Performance: The detection of chromosomal gains and losses in human tumors and 
other genetic diseases is medically important and has diagnostic, prognostic and therapeutic 
implications. We have shown that virtual karyotyping with Affymetrix SNP arrays is a robust 
and reliable alternative for chromosomal analysis of FFPE tissues showing high concordance 
with frozen tissues (1) and chromosomal analysis by conventional cytogenetics (2), and that 
it is useful in the identification of chromosomal abnormalities for classification of renal 
tumors (3). In our experience with more than 400 FFPE samples, the Affymetrix SNP arrays 
have demonstrated excellent performance and reproducibility with the 250K Nsp platform. 
We have shown that this technology can reliably detect chromosome copy number, LOH and 
aUPD in at least 76% of archival FFPE cases. Assay failure was linked to three major 
factors: older age of the sample, exposure to non-controlled temperature environments and 
sample institutional origin (4). 
 
1. Lyons-Weiler MA, Hagenkord JM, Sciulli CM, Dhir R, and Monzon FA. Optimization of the 
Affymetrix GeneChip Mapping 10K 2.0 Assay for Routine Clinical Use on Formalin Fixed 
Paraffin Embedded Tissues. Diag Mol Path 2008, 17: 3-13. PMID: 18303412 
2. Monzon FA, Alvarez K, Gatalica Z, Bridge JA, Nelson M, Kim HJ, Hagenkord JM. Detection of 
chromosomal aberrations in renal tumors: a comparative study of conventional cytogenetics and 


NCI Protocol #:  8727 
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81 
virtual karyotyping with SNP microarrays. Arch Pathol Lab Med. 2009 Dec;133(12):1917-22. 
PMID: 19961245 
3. Kim HJ, Shen SS, Ayala AG, Ro JY, Truong LD, Alvarez K, Bridge JA, Gatalica Z, Gonzalez-
Berjon JM & Monzon FA. Virtual-Karyotyping with SNP microarrays in morphologically 
challenging renal cell neoplasms: a practical and useful diagnostic modality. Am J Surg Pathol. 
2009 Sep;33(9):1276-86 PMID: 19461508 
4. Alvarez K, Kash SF, Lyons-Weiler MA, Kim HJ, Mathai B, Hagenkord JM and Monzon FA. 
Reproducibility and Performance of Virtual Karyotyping with SNP Microarrays for the Detection 
of Chromosomal Imbalances in Formalin-Fixed Paraffin Embedded Tissues. Diagn Mol Pathol 
(in press)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX H 
TISSUE MICROARRAY (TMA) 
 
1.  Collection of Specimen(s)   
If patient consents to optional procedure(s), at least 2 and as many as 5 formalin fixed 
paraffin embedded blocks from nephrectomy will be acquired from each patient participating 
in the study.  These blocks will be used for TMA analysis and for virtual karyotyping.   A 
detailed laboratory manual will be provided. 
 
2.  Handling of Specimens(s) 
Specimens need to be kept at ambient temperatures, and reasonable efforts should be 
undertaken to avoid exposure to temperature extremes.  If necessary, samples may be 
shipped on gel packs to avoid extreme temperatures. 
 
3.  Shipping of Specimen(s) 
Samples will be batch shipped to the University of Texas M. D. Anderson Cancer Center.  
All samples will be transported according to applicable IATA regulations.   
 
Samples will be shipped to: 
 
Sherie Hodges 
University of Texas M. D. Anderson Cancer Center 
1220 Holcombe Blvd, Room ACB7.2408 
Houston, TX 77030 
Tel 713-563-3173 
Fax 713-563-0572 
  
GuClinicalResearchLab@mdanderson.org 
 
4.  Site(s) Performing Correlative Study 
The analysis will be performed at the University of Texas M. D. Anderson Cancer Center.    
 
5.  Tissue Microarray Methods 
Archival paraffin-embedded tissue will be evaluated by the PI or a dedicated pathologist, to 
select for areas containing viable cells.  These areas will be used to construct TMAs.  
Technical work will be performed by a dedicated technician under the supervision of the PI 
and the pathologist.   
 
Arrays will be constructed from 3 sites within each tissue block.  The impact of heterogeneity 
on TMA readout validity has been assessed in other tissue types, with TMAs demonstrating 
comparable readout quality to standard immunohistochemical slides by using triplicate 
samples.   Using a Beecher TMA device, three 0.6mm cores will be punched into each donor 
block, and transferred to a custom generated paraffin recipient block. Five micron-thick 
sections will be placed on a standard glass slide and will be stained using standard 
immunohistochemical techniques.  Five m TMA sections will be mounted on slides, 
deparaffinized and hydrated.  Section is then blocked and steamed, and appropriate antibody 
titer is applied overnight, rinsed, and appropriate secondary antibody is applied, followed by 
more rinses.  DAB+ is then applied followed by rinse and DAB+ enhancer.  The slide is then 


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placed in Hematoxylin followed by rinsing and bluing.  Section is dehydrated; coverslip is 
placed.   
  
Arrays created as outlined in will be stained with antibodies against the following proteins 
and others that may be deemed clinically relevant: Total AKT, AKTS473, AKTT308, p70 S6K, 
S6, phospho S6, p27, NFkB, mTOR, phospho mTOR.     RCC-specific antibody optimization 
has already been performed by our lab.  
 
6.  Sample Analysis 
Once staining has been performed, sample quantitation will be performed using an Ariol 
Image analysis system.  Areas of viable tumor will be gated, and necrotic and nonviable 
regions masked.   Acquisition characteristics will be set by the PI and the core facility staff.  
Percentage involvement of core by stain of interest will be captured as a continuous variable.  
Averaging of triplicate samples will be performed for each case.  In the situation where 
significant outliers exist, scanning quality will be assessed and samples discarded if 
variability is due to low sample quality.    
 
7.  Statistical Analysis 
Statistical Analysis will be performed according to guidelines in Section 13.4 of the protocol. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX I 
CYTOKINE AND ANGIOGENESIS FACTOR ANALYSIS:  
AMADO ZURITA, COLLABORATOR  
 
1.  Collection of Specimen(s) 
Venous blood will be collected for Cytokine and Angiogenic factors as outlined below. 
 
Collect blood into 1x 10ml EDTA vacutainer (BD# 366457), 1 x 10ml SST vacutainer (BD# 
367985), and 2 x 8ml Sodium Citrate CPT vacutainers (BD# 362761) following institutional 
procedures.  All samples should be clearly labeled with the NCI Protocol Number, Subject 
Number, Specimen, and Timepoint using an indelible marker.  A detailed laboratory manual 
will be provided. 
 
2.  Handling of Specimens(s)  
 
Serum and EDTA treated Plasma Samples: 
Allow the SST vacutainer to clot for approximately 20 minutes at room temperature prior to 
centrifugation.  Centrifuge the SST and EDTA vacutainers at 1200xg for 20 minutes at 4°C.  
Remove the serum and plasma layers, respectively, and transfer to cryovials.  Freeze serum 
and plasma samples at or below -80°C until shipment.  
 
Sodium Citrated Plasma and Peripheral Blood Mononuclear Cell Layer (PBMC) 
Samples: 
Within two hours of collection, centrifuge the Sodium Citrate CPT vacutainers at 1500xg for 
20 minutes at 25°C using only a swing-out head rotor.  (Spinning CPT vacutaienrs in a fixed 
angle rotor may cause tube breakage).  Without disturbing the mononuclear cell layer (cloudy 
white layer) remove the upper plasma layer and transfer to cryovials.  Freeze plasma samples 
at or below -80°C until shipment.  Next, remove 1.5ml of the mononuclear layer and divide 
among two cryovials.  Add an equal volume of freezing media to each cryovial.  (Freezing 
media consists of 80% RPMI-1640 (Cambrex 12-167F) and 20% DMSO (Sigma D8418).  
Mix thoroughly.  Freeze PBMC cryovials overnight at -80°C using a controlled rate freezing 
container (Mr. Frosty™, Nalgene 5100-0001).  After 24 hours at-80°C, PBMC samples will 
be transferred to a liquid nitrogen freezer for long-term storage until shipment.  Note:  Sites 
that do not have access to liquid nitrogen storage will submit serum and plasma 
samples only. 
 
3.  Shipping of Specimen(s) 
Samples will be batch shipped on dry ice to the University of Texas M. D. Anderson Cancer 
Center.  All samples will be transported according to applicable IATA regulations.  A 
detailed laboratory manual, as well as sample collection kits/shipping supplies, will be 
provided. 
 
Samples will be shipped to: 
 
Sherie Hodges 
University of Texas M. D. Anderson Cancer Center 
1220 Holcombe Blvd, Room ACB7.2408 


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85 
Houston, TX 77030 
Tel 713-563-3173 
Fax 713-563-0572 
  
GuClinicalResearchLab@mdanderson.org 
 
 
4.  Site Performing Correlative Study:    
Samples will be analyzed at the University of Texas M. D. Anderson Cancer Center.   
 
5.  Brief description of methods.  
 
Multiplex bead assays (MBAs) will be analyzed using a BioPlex 200 machine (Bio-Rad) in 
the Blood-Based Biomarkers Laboratory (part of the Heymach’s laboratory) at M. D. 
Anderson Cancer Center. Commercially available, validate, pre-made mixtures of beads will 
be used. Currently the profile consists of:  1) Bio-Plex 27-plex cytokine panel (BioRad, Cat# 
M50-0KCAF0Y); 2) Bio-Plex 23-plex cytokine panel (BioRad, Cat# M50-005KMII); and 3) 
smaller bead sets for EGF, TGFalpha, MMP-9, and E-Selectin (Lincoplex, HCYTO-60K-02 
and HCVD1-67AK-02). Note that the final profile may be modified as new assays are 
developed. We have worked extensively with each of these assays in the past. [At this time, 
MBAs for osteopontin (OPN), IGF family members, Placental growth factor (PlGF), and 
several members of the VEGF family are in development and these factors would need to be 
assayed by ELISA (R&D Systems), volume permitting, if the MBAs are not available at the 
time of analysis. Because of sample volume constraints, a maximum of 3-5 ELISA assays 
can be conducted in addition to the MBAs.] Samples will be assessed in duplicate on the 
same plate. Plasma samples will be processed as per manufacturer’s instructions. The 
combined MBA analyses, therefore, require less than 200 microliters of plasma. ELISA 
assays will be conducted as per manufacturer’s instructions using a MicroQuant plate reader 
in the laboratory. For each plate, the standard curves will be assessed to ensure that the 
expected assay range is achieved (typically 0.2 or 2 pg/ml to 3,200 or 32,000 pg/ml 
depending on the marker) 
 
The following assays will be performed and others will be added as appropriate.  
 
Multiplex bead arrays 
Bio-Plex 27-Plex Panel (BioRad) Cat# M50-0KCAF0Y 
Bio-Plex 23-Plex Panel (BioRad) Cat# M50-005KMII 
 
3-plex for Luminex:  Human CVD Biomarker Panel 1, Catalog # HCVD1-67AK (MMP-9, 
sICAM-1, and sE-Selectin) 
 
ELISA 
Human Osteopontin (OPN) Quantikine ELISA Kit (R&D Systems) Cat#DOST00 
Human Soluble Carbonic Anhydrase IX ELISA Kit (R&D Systems) Cat#DCA900 
Human sVEGF R2/KDR Quantikine ELISA Kit (R&D Systems) Cat# DVR200 
Human Collagen IV EIA kit (Argutus Medical) Cat#BIO82 


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Statistical Analysis: 
We have investigated potential blood-based biomarkers in a randomized phase II trial of 
sorafenib vs. sorafenib and interferon. Using multiplexed bead assays (MBAs) and ELISAs 
to broadly assess a profile of cytokines and angiogenic factor (CAFs), we have identified 
plasma markers that predicted improved progression-free survival (PFS) in patients in each 
arm. A CAF signature, derived by combining individual markers, was more predictive than 
individual markers alone. In vitro studies and patient data suggest that CAFs may be 
regulated by tumor hypoxia, Akt/mTOR signaling, and other pathways. Based on this and 
additional studies in other cancer types, we hypothesize that broad profiling of CAFs in 
plasma of RCC patients can be used to identify groups of patients that receive different 
degrees of benefit from different therapeutic regimen. We also hypothesize that CAF 
profiling can identify markers of therapeutic resistance and tumor pathway activation. Our 
primary goal in this project is to develop predictive biomarkers of benefit (prolongation in 
PFS and overall survival, OS) using plasma specimens from this randomized phase II trial. 
 
For the multiplexed bead arrays, the data is assessed in the following manner. For each plate, 
the standard curves are assessed to ensure that the expected assay range was achieved. For 
each individual sample, the mean concentration is calculated for duplicate samples, and the 
coefficient of variance % (CV%) is calculated for all analytes. If the median CV% was 
greater than 25%, analysis of the sample is repeated. In the rare case that the repeat CV% 
was greater than 25%, one of the two analyses is selected based on lower CV% and 
consistency with prior values.  


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The multiplexed beads are assessed in a similar manner. For each plate, the standard curves 
are assessed to ensure that the expected assay range was achieved. For each individual 
sample, the mean concentration is calculated for duplicate samples, and the CV% is 
calculated. If the CV% for an individual sample is greater than 50%, the value is rejected. 
 
Two important issues impacting the potential utility of the CAF profiling are baseline 
variability and stability during storage and freeze-thaw cycles.  To investigate these issues, 
we assessed two baseline plasma specimens (taken ~1 week apart) from 163 patients and 65 
patients in two lung cancer trials, and two additional baseline serum samples from 144 
patients in a separate trial.  We found a high degree of correlation between the two baseline 
values. As expected, serum levels of VEGF were higher than plasma. We also assessed the 
effect of 1-4 freeze-thaw cycles or of storage at 4 °C for 48 hours compared to first thaw 
levels.  Levels of all but one CAF (IL-5) were relatively stable (<20% change under these 
conditions), suggesting that CAF profiles should be relatively stable over 1-2 thaw cycles. 
 
We are interested in changes in CAF levels from baseline (BL) that are associated with either 
tumor progression or are predictive of PFS. It is expected that approximately 80% of the 
patients will complete cycle 2. To identify potential markers of therapeutic resistance, we 
will fit linear mixed-effects models for each marker that is measured. These models will 
incorporate random effects that allow each individual patient to have his or her own natural 
level as well as a fixed binary effect for “progressed” versus “not progressed.” The 
significance of the fixed effect of progression is measured by an F-test. We will also explore 
more elaborate models that allow for a treatment effect that may distinguish changes on 
treatment from BL. To correlate changes in individual CAFs with clinical benefit from 
MK2206 vs. Everolimus, we will use Cox proportional hazards models. Primary analyses 
will use the differences in marker levels as continuous predictors. We will also explore the 
use of derived binary markers (“changed” or “unchanged”), where the thresholds for change 
will be set using mixed-effects linear models that incorporate repeated measures on the same 
individual patient. For the evaluation of markers to predict clinical benefit, we will take 
individual predictive markers and will combine them with the goal of identifying groups of 
patients with greater PFS and/or benefit. We will apply two different methods of analysis. 
First, we will fit multivariate Cox proportional hazards models that incorporate all individual 
markers that exhibit some predictive ability, using the Akaike Information Criterion (AIC) to 
eliminate markers that do not contribute significantly to the multivariate model. Second, we 
will apply robust clustering methods to identify subgroups of samples that exhibit similar 
CAF expression profiles, and test whether the resulting subgroups have different outcomes. 
 
 
 
 
 
 
 
 


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APPENDIX J 
MSKCC RISK STRATIFICATION 
 
MSKCC Risk Stratification 
Karnofsky Performance Status 
< 80 
Corrected Calcium 
> 10.0 mg/dL 
Hemoglobin 
  
< Lower Limit of Lab Reference Range 
 
Risk Groups 
Favorable 
0 Risk Factors 
Intermediate 
1 Risk Factor 
Poor 
  2 or 3 Risk Factors 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX K 
MULTI-CENTER STUDY MANAGEMENT PLAN  
 
Multi-Center Study Management Plan  
 
For 
 
National Cancer Institute (NCI) / 
Cancer Therapy Evaluation Program (CTEP)Phase I/II & Phase II  Studies 
Version 4/10 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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90 
 
Table of Contents 
 
 
 
 
 
1.0    
Introduction 
 
 
 
 
 
3 
 
2.0 
Purpose  
 
 
 
 
 
3 
 
3.0 
General Roles and Responsibilities 
 
 
 
 
3.1 
MD Anderson Cancer Center Principal Investigator  
3 
 
 
Protocol Development 
 
 
Study Oversight 
 
 
 
 
 
Research Team Teleconferences  
 
 
3.2 
MD Anderson Cancer Center NCI Support Services  
4 
 
 
Administrative Support  
 
 
Regulatory Management  
 
 
 
Regulatory Document Collection 
 
 
Study Management Support 
 
 
Data Management Support 
 
 
Quality Assurance 
 
 
3.3 
Participating Institution Principal Investigator 
 
5 
 
 
Regulatory Compliance 
Study Contact List 
NCI Investigator Registration 
IRB Approval 
Regulatory Documents 
Adverse Events 
IND Safety Reports 
 
 
Study Management 
 
 
 
Eligibility 
 
 
 
Protocol Compliance 
 
 
Data Collection 
 
 
 
Patient Registration 
 
 
 
Data Entry 
 
 
 
Data Locks 
 
4.0 
Patient Confidentiality and Authorization Statement 
 
9 
 
5.0 
On-Site Audit 
 
 
 
 
 
10 
 
 
Purpose of Audit 
 
 
Selection for Audit 
 
 
Audit Notification 
 
 
Responsibilities of Participants in the Audit 
 
 
Conducting the Audit 
 
 
Audit Findings 
 
 
Audit Summary and Outstanding Corrective Action Items 
 
 
Audit Outcome 


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1.0 
INTRODUCTION 
 
This Study Management Plan (SMP) outlines the procedures and requirements for institutions 
collaborating with MD Anderson Cancer Center (MDACC) in the conduct of a National Cancer 
Institute (NCI)/Cancer Therapy Evaluation Program (CTEP) sponsored research protocol. 
 
2.0 
PURPOSE 
 
To establish standards that will ensure compliance with Federal Regulations, Good Clinical 
Practice (GCP) Guidelines; and Health Insurance Portability and Accountability Act (HIPAA) 
requirements in accordance with the CTEP Multicenter Guidelines. 
 
 
3.0 
GENERAL ROLES AND RESPONSIBILITIES 
 
In accordance with the CTEP Multicenter Guidelines, the MDACC Principal Investigator, 
MDACC NCI Support Services (MDACC NCISS), and the participating institution will all agree 
to the general responsibilities as follows (specific procedures for these general responsibilities 
are detailed in the SMP): 
 
3.1 
MDACC Principal Investigator (MDACC PI) 
 
The MDACC PI will accept responsibility for all aspects of the Study Management Plan to 
include: 
 
Protocol Development 
• Oversee the coordination, development, submission, and approval of the protocol as 
well as subsequent amendments by the NCI and the MDACC IRB. 
 
• List each participating investigator and institution on the protocol title page including 
address, phone number, and email and designate the lead institution on the title page. 
 
• Assure all participating institutions are using the correct version of the protocol. 
 
Study Oversight 
• Monitor progress and overall conduct of study at all participating institutions.  
 
• Ensure all CTEP reporting requirements are met.  
 
• Review data and maintain timely submission of data for study analysis.  
 
• Research Team Teleconferences: The MDACC PI & research team, MDACC 
NCISS, and participating institution PI and research staff will participate in a 
teleconference every 2 – 4 weeks, as needed, and will discuss the following information 


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• Patients enrolled at participating sites including 
o Brief history 
o Eligibility for trial 
o Status of treatment 
o Adverse Events 
o Response evaluation 
 
• Review of safety data 
o Unexpected toxicities 
o Serious Adverse Events 
o IND safety reports 
 
3.2 
MDACC NCI Support Services (MDACC NCISS) 
 
To assist the MDACC PI in meeting his/her responsibilities MDACC NCISS will assume the 
following general responsibilities: 
 
Administrative Support 
• Act as the central liaison between the MDACC PI, participating institution, and NCI 
CTEP/PIO Office. 
 
• Maintain a contact list of all study participants at MDACC and the participating 
institution. 
 
Regulatory Management 
• Distribute approved protocols to participating institutions, notify them of amendments, 
and provide them with copies of approved amended protocols. 
 
• Ensure that each participating institution has the appropriate assurance on file with the 
Office of Human Research Protection (OHRP form 310) and this has been submitted 
to the CTEP PIO. 
 
Regulatory Document Collection:  Refer to Section 3.3 for a list of documents that must be 
submitted to MDACC NCISS prior to protocol activation and submitted on an ongoing basis 
for the duration of the study. 
 
Study Management Support 
• Conduct study initiation meetings with MDACC PI and provide support to the 
participating institution research staff, as required. 
 
• Distribute external Serious Adverse Event safety reports to participating sites. 
 
• Notify participating institutions of protocol hold or closure. 
 
 


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Data Management Support 
• Provide participating sites with access, training, and support for electronic data entry. 
 
• Notify participating institution research teams of data locks prior to quarterly data 
transmission due dates 
 
• Monitor data quality and issue data queries / error log findings. 
 
Quality Assurance 
• Coordinate and participate in regularly scheduled teleconferences with the MDACC 
PI, the participating institution PI and their respective research teams to review study 
conduct. 
 
• Audit participating institutions by on-site inspection of selected patient records and / or 
by requesting source documents and research records as requested.  
 
3.3 
Participating Institution Principal Investigator 
 
The general responsibilities for each participating institution are as follows: 
 
Regulatory Compliance 
• Study Contact List: Provide a list of key study personnel and update MDACC NCISS 
with research staff changes on a timely basis. 
 
• NCI Investigator Registration: Maintain an active NCI Investigator Registration 
number for any physician who will be consenting / treating patients to the study and 
provide confirmation of annual renewal.  
 
• IRB Approval: Submit protocol and amendments to local IRB prior to initiating any 
protocol activity / changes. 
Note: If IRB approval for amendments is not obtained within the timeframe 
specified at time of amendment distribution accrual will be suspended until IRB 
approval is obtained. 
 
• Regulatory Documents: Provide copy of required regulatory documents to MDACC 
NCISS prior to activation. 
 
1. Federal Wide Assurance (FWA) number 
2. Laboratory certifications (CLIA / CAP) 
3. Normal laboratory values 
4. NCI Investigator Registration Number/expiration dates for all physicians  
5. Delegation of authority log 
6. Copy of initial IRB approval documents 
 
The following regulatory documents must be submitted on an ongoing basis for the duration 
of the study: 


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1. Copy of IRB annual approval documents.  Note:  If IRB annual approval is 
not received prior to the anniversary of the previous approval, accrual will 
be suspended until the annual approval is received. 
2. Copy of IRB approval documents for any protocol or informed consent 
revisions.  Note:  If IRB approvals for amendments are not received within 
the timeframe indicated at the time of distribution, accrual will be 
suspended until IRB approval is obtained. 
3. Confirmation of renewal of NCI Investigator Registration Number 
4. Copy of CTEP-AERS reports for Serious Adverse Events 
5. Evidence of IRB review of external safety reports 
6. Protocol violations and deviations submitted to the participating institution 
IRB. 
7. Copy of all signed informed consents for patients enrolled on the trial, if 
requested by the MDACC PI. 
8. Copy of IRB approval documents for any protocol status changes:  
activation, study closed to new patient enrollment, study closure, study 
termination.  Note:  If IRB annual review is not provided on or before the 
anniversary of the previous approval, accrual will be suspended until the 
annual re-approval is received. 
 
 
 
• IND Safety Reports: MDACC NCISS will distribute IND safety reports and 
appropriate guidance regarding IRB submissions and patient notification to the 
participating institutions.   
 
 
 
Study Management 
• Eligibility: Ensure patients meet all eligibility criteria prior to registering the patient 
on study. 
 
• Adverse Events: Submit Expedited Adverse Event reports directly to CTEP (via 
CTEP-AERS) as required per protocol and provide copies to the MDACC PI and 
NCISS. Submit Routine Adverse Events via Clinical Oncology Research System 
(CORe.) 
 
• Protocol Compliance: Adhere to the MDACC IRB definition of protocol deviation 
and protocol violation and requirements for reporting. 
 
Protocol Deviation: Noncompliance with the protocol that does not have a 
significant effect on the subject’s rights, safety, welfare, and/or the integrity of 
the data. Deviations may be caused by the action of the subject, the 
investigator, the research staff, or natural events. 
 
Protocol Violation: Changes to protocol procedures without prior approval of 


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the IRB/Sponsor. These changes may have a significant effect on the subject’s 
rights, safety, welfare, and/or the integrity of the data, and may cause an 
unanticipated problem to the subject or others. Violations may also 
significantly alter the clinical effectiveness of the treatment or the evaluation of 
its toxicity.  
 
Procedures for Reporting Protocol Violations/Deviations  
 
Participating Institutions: Protocol violations/deviations occurring at a 
participating institution will be submitted to that site’s own IRB.   A copy of 
the participating institution’s IRB violation/deviation report will be forwarded 
to the MDACC NCISS within 7 calendar days after the original 
submission.  
 
Coordinating Center:  Upon receipt of the violation/deviation report from the 
participating institution, MDACC NCISS will submit the report to the MDACC 
PI for review.  
 
 
Data Collection 
 
The Clinical Oncology Research System (CORe) is a web based database that is used for 
patient registration (for Phase I, Phase I/II and Phase II trials) and data entry (for Phase I/II, 
II trials).  CORe can be accessed at www.oncologyresearch.org .  Study staff at 
participating institutions will be provided with a username and password for CORe at the 
time of study activation. 
 
  
 
• Patient Registration: All patients, regardless of the phase of the trial, will be registered 
in CORe prior to beginning treatment.   
At the time of registration portions of a patient’s protected health information 
will need to be entered. In order for the site to enter this information the patient 
must have signed an informed consent document, which includes an 
authorization for the release of protected personal health information (IC/A). 
The authorization that each institution obtains to use and disclose protected 
health information must include MD Anderson Cancer Center as an entity that 
they will share data with. This consent and authorization (IC/A) document 
authorizes MD Anderson Cancer Center to collect and retain documents, 
reports, and/or information which relate to the patient’s participation on the 
protocol. This document also authorizes MD Anderson Cancer Center to send 
data and/or composite data for the entire study to each site participating in the 
trial.  
 
• Data Entry: Enter data in CORe according to the following data schedule 
 


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At time of registration 
(Phase I/II and II trials) 
• Assign patient number 
• Name & demographics 
• Eligibility checklist 
 
Within 1 week of 
registration 
(Phase I/II and II trials) 
• Pre-study data including 
o Registering institution  
o Disease subgroup code (NCI CDU)  
o Disease code (NCI CDU)  
o Payment method (NCI)  
o Zubrods PS  
o Baseline abnormalities 
o Prior therapy 
o Number of prior chemo regimens  
 
 
Within 3 weeks after the 
completion of each cycle. 
 (Phase I/II and II trials) 
• Treatment Course 
o Course Number 
o Cycle start date 
o Treatment code (NCI CDU) 
o Height (cm) 
o Weight (kg) 
o AE Experienced 
o Treating institution 
• 
Treatment Agent 
o Agent code (NCI CDU) 
o Total dose this course 
o Dose change 
 
• Adverse Events 
o Adverse event 
o Symptoms (required if AE other used) 
o Grade 
o Onset date 
o Resolved date 
o Relationship 
o AE report sent to CTEP 
 
Within 1 week after the 
completion of the cycle 
required for response 
assessment 
(Phase I/II and II trials) 
• Protocol Summary 
o Last dose date (date of last treatment) 
o Off treatment reason (if applicable) 
o Evaluability 
o Evaluable for response 
o Protocol response 
o Response date 
o Progression date (if applicable) 
Within 1 week after 
• Off Protocol 


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completing treatment or 
taken off study 
(Phase, I/II and II trials) 
o Off date 
o Death date (if applicable) 
o Death date source 
o Death comment 
o Cause of death 
 
Specifics Regarding Phase II Trials 
• Data Locks: Data will be transmitted to NCI quarterly on January 31, April 30, July 
31, and October 31.  Approximately 3 weeks prior to the transmission date, the 
participating institution will be informed by MDACC NCISS that the data will be 
locked during data transmissions.  During this period of data lock, no new patient 
data and/or changes to previously entered data should be made unless instructed by 
MDACC NCISS.  
 
• Data Queries: Following data transmission NCI will issue an error log to MDACC 
NCISS detailing any corrections that need to be made to data prior to protocol 
acceptance.  MDACC NCISS will communicate the required changes to the 
participating institution. NCISS will periodically review the data for completeness. 
You may receive queries directly from NCISS prior to data submission to the NCI. 
Required data corrections must be completed as instructed by MDACC NCISS.  
 
 
4.0 
PATIENT CONFIDENTIALITY AND AUTHORIZATION STATEMENT 
 
The Health Insurance Portability and Accountability Act of 1996 contains,  as one of its six major 
components, the requirement to create privacy standards for health care information that is used 
or disclosed in the course of treatment, payment or health care operations.  The original Privacy 
Rule, as it has come to be known, was published in December 2000.  The Final Rule was published 
on August 14, 2002, which has modified the privacy rule in significant ways vis-à-vis research. 
 
In order for covered entities to use or disclose protected health information during the course of 
an MDACC Multicenter trial the participant in the trial must sign an authorization form.  This 
Authorization may or may not be separate from the Informed Consent.  The Authorization may 
require local IRB approval before presentation to a potential trial participant.  The participating 
institution, with the approval from the NCI/CTEP and MDACC, will provide an Informed Consent 
template, which covered entities, must use.  
 
MDACC and participating institutions will attempt to limit its use of protected health information 
in its trials.  However, because of the nature of these trials, certain protected health information 
must be collected per National Cancer Institute requirements. These are the primary reasons why 
MDACC has chosen to use Authorizations, signed by the participant on the trial, rather than limited 
data sets with data use agreements.  
 
 
5.0 
ON-SITE AUDITING 
 


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Purpose of Audit 
 
To ensure that the data analyzed to determine study results accurately reflect the primary 
source documents and that any clinical study was conducted in accordance with an 
Institutional Review Board (IRB)-approved protocol. The audit program reviews 
protocol management in the following categories: eligibility, informed consent, 
treatment, disease outcome/response, toxicity, and general data quality. Compliance with 
all federal, National Cancer Institute and institutional requirements for the protection of 
human subjects is also assessed.  
 
In addition, the audit program provides education to the research staff regarding issues 
identified during the audit and assists research teams to develop appropriate ways to 
correct deficiencies identified by the audit.  
 
 
Selection for Audit 
 
Participating institutions can be selected for audit at any time.  Audit will generally be 
performed on a random basis and may occur at 6 – 12 month intervals. 
 
 
Audit Notification 
 
The participating institution principal investigator (PI) and study coordinator shall be 
notified two to four weeks in advance of the audit start date.  If the audit is initiated due 
to suspected deficiencies the advance notice may be shorter than 2 weeks.  All audit 
notifications shall be delivered to the PI and study coordinator by e-mail.  It is important 
that a person who is familiar with the research protocol and the study subjects enrolled 
on the trial be available (but not necessarily present) during the audit to assist the 
auditors in locating documentation that may be difficult to find in the primary medical 
record.  
 
The notification will include: 
• The date of the audit 
• A list of the patient records to be audited 
• A list of documents required for the audit 
 
 
Responsibilities of Participants in the Audit 
 
Clinical Trials Auditors: If more than one auditor visits the site a lead auditor will be 
designated to guide the audit process.  It shall be the auditor’s responsibility to print a 
copy of the protocol and be familiar with the study prior to the start of the audit. 
 
 


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Principal Investigator and Research Staff: The principal investigator is responsible for 
assuring that all requested audit materials are available at the time of the audit.  These 
materials shall include the following: 
 
• One copy of an original signed and dated informed consent document (ICD) 
for each participant. For patients who have been re-consented while on study, 
an original signed and dated informed consent must be available for each 
IRB-approved version of the informed consent. 
• All patient records:  in-patient charts (if applicable), protocol-specific patient 
source documents (signed and dated pill diaries, symptom records), database 
printouts, and patient research files 
• Correspondence and source documentation from outside institutions 
pertaining to patient research data 
• Radiology films and other specified studies, if requested 
• Any operative, pathology and radiotherapy reports required by protocol 
• Regulatory Binder 
 
  
The research staff must have all patient research charts and the Regulatory Binder 
organized in a systematic and consistent fashion. The presence of organized study records 
reduces the potential for queries and helps prevent repeated questions to the study 
coordinator / PI requesting assistance in locating items during the audit.  
 
 
Conducting the Audit 
 
Medical Record Review: At the time of the medical record audit, source documentation 
shall be reviewed and used to independently verify study data. Data quality shall be 
assessed by measuring it against the standards for optimal data collection as defined in 
the research protocol.  Data entered in CORE should match precisely with the 
corresponding information on the primary source document.  
 
The research team shall also be evaluated on protocol compliance with the study 
schedule, regulatory requirements, and guidelines for Good Clinical Practice (GCP).  
Although the PI may delegate responsibilities for various aspects of the protocol 
management, the PI alone retains ultimate responsibility for the conduct of the clinical 
trial. 
 
The following elements are reviewed during the audit: 
 
Activation/Continuing Review Information: The auditor shall verify that: 
• IRB approval has been obtained prior to study activation and patient enrollment;  
• An annual continuing review has been completed within 365 days from initial 
date of approval;  
• Confirmation that all consenting physicians have a current NCI Investigator 
Registration number 


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• Protocol amendment, informed consent, and IRB approval dates are appropriate;  
• Patients were treated following CORe registration. 
• All regulatory documents are in the regulatory binder(s) 
 
Informed Consent Document:  The ICD must: 
• Be the appropriate IRB-approved version at the time the patient was enrolled. For 
NCI studies, the ICD must also have received NCI’s approval before it is used in 
obtaining informed consent.  
• Contain the patient’s signature and date; 
• Contain the signature and date of the person who is obtaining the informed 
consent; 
• Contain the signature of the witness and date it was signed; if applicable 
• Indicate selection of optional studies verified by patient initials  
• List M. D. Anderson as an authorized reviewer on ICD's from outside institutions 
(where M. D. Anderson serves as the lead institution on a multicenter trial). On 
multicenter trials where M. D. Anderson is not the lead site, any institution that 
may request protected health information should be listed in the HIPAA section of 
the M. D. Anderson ICD. 
 
The informed consent process must be documented in the on-study note located in each 
patient’s medical record. 
 
Eligibility: The eligibility checklist is compared against the primary medical record to confirm 
that all criteria were met prior to registration on the trial. If documentation cannot be located, 
eligibility is noted as “unable to confirm” due to insufficient data. The patient shall be 
considered ineligible if one or more of the eligibility requirements were not satisfied.  
 
Protocol Compliance: Source documentation is used to verify that the performance status has 
been assessed and that the results of all required tests have been obtained within the protocol-
specified time frame prior to the start of treatment. On-study visits, lab tests, and diagnostic 
studies shall be checked for adherence to the study schedule. If testing or visits were missed, 
the auditor shall verify that a protocol deviation/violation report was completed for each 
occurrence and submitted to the IRB, and a copy placed in the Regulatory Binder. A deviation 
log may be utilized as per institutional policy. 
 
Treatment Administration:  The audit team confirms that patients receive the correct dose, 
route, dosing interval, and timing of the treatment administered.  Dose modifications shall also 
be checked and compared against the protocol.  The auditor shall assure that the proper body 
surface area (BSA) was calculated. The auditor shall also check the medical record for correct 
and consistent recording of the study subject’s weight and shall look for dose adjustments 
based on body weight changes as defined in the protocol.  
 
Disease Outcome / Response: The auditor shall verify baseline and on-study disease status by 
reviewing tumor measurements analyses in the medical record/research file. Solid tumor 
measurements shall be compared to imaging reports and/or original radiology films to confirm 
tumor response. For hematologic tumors, documented response shall be verified using 


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appropriate analyses as stated in the protocol. If the auditor cannot verify the outcome 
response, a physician auditor shall be consulted for a final decision. 
 
Toxicity: All toxicities shall be documented in the medical record or recorded on patient data 
forms.  These shall include the appropriate Common Toxicity Criteria term to describe the 
toxicity, the grade of toxicity, the attribution, date of onset, and date of resolution.  The auditor 
shall confirm that all patients have been followed for toxicities for thirty days from the last 
date of protocol therapy. When a SAE occurs, the auditor shall verify that initial and follow-
up reporting is appropriate as required in the Code of Federal Regulations and in accordance 
to NCI / CTEP’s policy. 
 
General Data Quality: This category concerns the quality and completeness of source 
documentation as well as the accuracy of data transcription from the source document to the 
case report form.  Emphasis shall be placed on clear and complete reporting of the findings 
and correct matching of all data elements.  Any inconsistent, incomplete, illegible, or hard to 
follow records shall be noted.  Comments shall be made regarding repeated discrepancies that 
appear to affect the validity of the data or indicate that the management of the protocol needs 
more oversight. 
 
Audit Findings 
 
• Following completion of the audit, a preliminary audit findings report will be completed 
and be presented at the Audit Findings meeting or the “Exit Interview meeting”. 
• The purpose of the exit interview is to provide an opportunity for education, clarification, 
immediate dialogue, and feedback. It is not intended as a time to resolve all of the issues 
noted in the audit findings. 
• The principal investigator and the study coordinator responsible for the study being audited 
are required to attend.  Additional research staff associated with the study is encouraged to 
attend as well. 
• As time allows, the lead auditor shall educate the research team in interpretation of the 
various regulatory requirements / institutional policies and shall provide guidance on the 
development of a corrective action plan to address issues involving major deficiencies. 
• At the conclusion of the exit interview, the lead auditor may also discuss best practice 
guidelines and offer suggestions for improvement on data collection and protocol 
management.   
• Following the exit interview the lead auditor shall amend the audit findings to include any 
corrections/clarifications noted during the exit interview.    
• Once the audit findings have been modified, the lead auditor shall send a return receipt e-
mail containing a copy of the audit findings to the PI and study coordinator.   
• Upon receipt of the e-mail, the research team shall have two weeks to respond and return 
the audit findings to the lead auditor.   
• The PI/study coordinator shall be responsible for providing a written response to each of the 
findings cited during the audit. 


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• To properly respond to the audit findings, the research team must enter a response 
immediately below each query.  All research team responses shall be entered in red directly 
onto the audit findings document.   
• When appropriate, a corrective action plan shall be included to complete the response. 
• In situations where the lead auditor must review a source document to verify a research team 
response, the study coordinator shall provide a photocopy of this source document. All 
photocopies must be provided to the lead auditor by the deadline for audit response noted in 
the e-mail. 
• Once all of the queries have been addressed and the response is complete, both the 
individual preparing the document and the PI for the study must print out and sign 
one copy of the audit findings report.  An electronic copy of the same document shall 
be e-mailed to the lead auditor.  
• Once the lead auditor receives the electronic copy of the response to the audit findings, he or 
she shall review the explanations/corrective action plans and shall create a summary report 
of outstanding audit findings, PI responses and any other audit activities. 
• The final audit report will be forwarded to the Lead PI, the MD Anderson IRB and the 
Quality Improvement Oversight Committee (QIOC) for review.  
•  The QIOC is a multi-disciplinary committee at MD Anderson that examines the 
findings of protocol audits to evaluate for the presence of system issues that may require 
further action.