Androgen Receptor Modulation Phase II, Randomized Study of MK-2206 - Bicalutamide Combination in Patients With Rising PSA at High-Risk of Progression After Primary Therapy
Phase: PHASE2
Conditions: Recurrent Prostate Carcinoma, Stage I Prostate Cancer AJCC v7, Stage IIA Prostate Cancer AJCC v7, Stage IIB Prostate Cancer AJCC v7, Stage III Prostate Cancer AJCC v7
Sponsor: National Cancer Institute (NCI)

i 
 
 
 
Group Chair: Robert L. Comis, M.D. and Mitchell Schnall, M.D. 
Group Statistician: Robert Gray, Ph.D. and Constantine Gatsonis, Ph.D. 
Jean MacDonald, Director of Research Operations 
Mary Steele, Director of Group Administration 
July 31, 2014 
 
Martha Kruhm, MS RAC 
Head, Protocol and Information Office 
Quality Assurance Section 
CTEP, DCT, NCI 
6130 Executive Blvd, EPN Room 7000 
Bethesda, MD   20892 
Dear Ms. Kruhm: 
Enclosed is Addendum #9 to E2809, Androgen Receptor Modulation Phase II, Randomized 
Study of MK-2206 - Bicalutamide Combination in Patients With Rising PSA at High-Risk of 
Progression After Primary Therapy. 
The following revisions to E2809 protocol have been made in this addendum: 
 
Section 
Change 
1. 
Cover Page 
Updated the version date. 
2. 
Section 6.1.4 
Inserted into the first and second bullet points the phrase "confirmed on 
two consecutive additional determinations taken at least 4 weeks apart," to 
more clearly define undetectable PSA. 
The following revisions to E2809 Informed Consent Document have been made in this 
addendum: 
 
Section 
Change 
1. 
Cover Page 
Updated the version date. 
2. 
"What side effects or 
risks can I expect from 
being in the study?" 
Updated the risk section language to correspond with the condensed 
risk lists format. 
3. 
"What side effects or 
risks can I expect from 
being in the study?" 
Inserted condensed risk list for Bicalutamide. 
If you have any questions regarding this addendum, please contact 
hays.elizabeth@jimmy.harvard.edu or 617-632-3610. 
We request review and approval of this addendum to E2809 so ECOG-ACRIN may activate it 
promptly.   
Thank you. 
Sincerely, 
Pamela Cogliano 
Protocol Development Manager 
ECOG-ACRIN Operations Office – Boston  
Frontier Science 
900 Commonwealth Avenue Boston, MA 02215 
(617) 632-3610 Fax: (617) 632-2990 
Randomization: (617) 632-2022 

ii 
Enclosure 
CC: Anna C. Ferrari, M.D. 
Ron Rodriguez, M.D. 
Michael Carducci, M.D. 
Glenn Liu, M.D. 
Yu-Hui Chen, M.P.H., M.S. 
James Corkery 
Tanya Mustacchio 
Khemraj Hirani, MPharm, PhD, RPh, 
CPh, CCRP, MBA 
Michelle Hobbs, PharmD 
Mark D. Walsh, PharmD, BCOP 
 
Carol Chami, R.N. 
Mary Vienneau 
Kerry Higgins 
Laura Gagnon 
Mary Steele 
Jean MacDonald 
Mary Bonds, MPH 
Elizabeth Hays 
Lauren Lambert 
Adekunle A. Raji 
Maddy Balois Oulette 
 
 

E2809 
 
1 
Androgen Receptor Modulation 
Phase II, Randomized Study of MK-2206 - Bicalutamide Combination 
in Patients With Rising PSA at High-Risk of Progression 
After Primary Therapy 
STUDY CHAIR: 
Anna C. Ferrari, M.D. 
STUDY CO-CHAIR: 
Ron Rodriguez, M.D. 
STUDY STATISTICIAN: 
Yu-Hui Chen, M.P.H., M.S. 
GU COMMITTEE CHAIR: 
Michael Carducci, M.D. 
PROSTATE SUB-COMMITTEE CHAIR: 
Glenn Liu, M.D. 
Version Date:  July 31, 2014 
NCI Update Date:  July 2, 2013 
 
 
 
ACTIVATION DATE 
 
 
December 23, 2010 
 
 
Update #1 – 3/11 
 
 
Addendum #1 – 4/12 
 
 
Addendum #2 – 4/12 
 
 
Addendum #3 – 7/12 
 
 
 
Addendum #4 – 9/12 
 
 
 
Update #2 – 9/12 
 
 
 
Addendum #5-2/13 
 
 
 
Update #3 – 2/13 
Addendum #6 – 6/13 
Addendum #7 – 6/13 
Update# 4 – 7/13 
Addendum #8 – 6/14 
 
 
 
Addendum #9 - 10/14 
 
NCI Supplied Agents: 
MK-2206 (NSC 749607; IND 109493) 
Commercial Agents: 
Bicalutamide (Casodex) 
 
Rev. 4/12 
Rev. 4/12 
Rev. 3/11 
Rev. 6/14 

ECOG-ACRIN 
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Version Date: July 31, 2014 
 
NCI Update Date: July 2, 2013 
2 
Table of Contents 
Schema ...................................................................................................................... 5 
1. Introduction ........................................................................................................ 6 
1.1 Prostate Cancer ......................................................................................... 6 
1.2 Androgen Receptor in Prostate Cancer .................................................... 6 
1.3 The PI3K/PTEN/AKT/mTor pathway.......................................................... 7 
1.4 Clinical Experience with Non-Castrating Peripheral Androgen Blockade 
Strategies ................................................................................................ 10 
1.5 Nadir PSA Response to Castration and Outcome ................................... 11 
1.6 Molecular Features and Response to Therapy ....................................... 12 
1.7 Rationale and Hypothesis ....................................................................... 12 
1.8 MK-2206 .................................................................................................. 12 
1.9 Selection Criteria ..................................................................................... 19 
1.10 Gender and Ethnicity .............................................................................. 20 
2. Objectives ......................................................................................................... 21 
2.1 Primary .................................................................................................... 21 
2.2 Secondary ................................................................................................ 21 
2.3 Laboratory Studies Objectives ................................................................ 21 
3. Selection of Patients ......................................................................................... 22 
3.1 Eligibility Criteria ..................................................................................... 22 
4. Randomization Procedures ............................................................................... 27 
4.1 Protocol Number ..................................................................................... 29 
4.2 Investigator Identification ....................................................................... 29 
4.3 Patient Identification .............................................................................. 29 
4.4 Eligibility Verification .............................................................................. 29 
4.5 Stratification Factors ............................................................................... 30 
4.6 Additional Requirements ........................................................................ 30 
4.7 Investigator Drug Brochure and Safety Alerts ........................................ 30 
4.8 Instructions for Patients who Do Not Start Assigned Protocol Treatment30 
5. Treatment Plan ................................................................................................. 31 
5.1 Administration Schedule ......................................................................... 31 
5.2 Adverse Event Reporting Requirements ................................................. 33 
5.3 Comprehensive Adverse Events and Potential Risks list (CAEPR) for MK-
2206 (NSC 749607) .................................................................................. 42 
5.4 Dose Modifications ................................................................................. 45 
5.5 Supportive Care ....................................................................................... 48 
5.6 Duration of Therapy ................................................................................ 48 
5.7 Discontinuation of Therapy ..................................................................... 50 
5.8 Duration of Follow-up ............................................................................. 50 
6. Measurement of Effect ..................................................................................... 51 
6.1 Biochemical Response ............................................................................. 51 

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6.2 Clinical Progression ................................................................................. 51 
6.3 Survival .................................................................................................... 51 
6.4 Time to PSA Progression ......................................................................... 51 
6.5 Time to PSA Nadir ................................................................................... 52 
6.6 PSA Slope................................................................................................. 52 
6.7 Symptomatic Deterioration .................................................................... 52 
6.8 Duration of Response .............................................................................. 52 
7. Study Parameters .............................................................................................. 53 
7.1 Therapeutic Parameters.......................................................................... 53 
8. Drug Formulation and Procurement ................................................................. 55 
8.1 MK-2206 .................................................................................................. 55 
8.2 Bicalutamide (Please refer to the package insert for more 
comprehensive information.) ................................................................. 58 
9. Statistical Considerations .................................................................................. 59 
9.1 Study Design/Primary Endpoints ............................................................ 59 
9.2 Secondary Endpoints............................................................................... 59 
9.3 Accrual ..................................................................................................... 60 
9.4 Safety Monitoring ................................................................................... 60 
9.5 Gender and Ethnicity .............................................................................. 61 
10. Correlative Studies ............................................................................................ 62 
10.1 Sample Submissions ................................................................................ 62 
10.2 ECOG-ACRIN Sample Tracking System .................................................... 63 
10.3 Banking .................................................................................................... 63 
10.4 Sample Inventory Submission Guidelines ............................................... 64 
11. Records to Be Kept ............................................................................................ 65 
11.1 Records Retention ................................................................................... 65 
12. Patient Consent and Peer Judgment ................................................................ 65 
13. References ........................................................................................................ 65 
Appendix I  Informed Consent Template for Cancer Treatment Trials (English 
Language) [Deleted in Addendum #5] .............................................................. 74 
Appendix II  Pathology Submission Guidelines ....................................................... 75 
Appendix III  Patient Thank You Letter .................................................................... 81 
Appendix IV  Patient Medication Calendar (Pill Diary) ............................................ 82 
Appendix V  Cooperative Research and Development Agreement (CRADA) .......... 86 
Appendix VI  List of CYP3A4 Inhibitors and Inducers .............................................. 88 
Appendix VII Medications That May Cause QTc Prolongation ................................ 90 
Appendix VIII  Performance Status Criteria ............................................................. 92 
 

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NCI Update Date: July 2, 2013 
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STUDY CHAIR 
STUDY CO-CHAIR 
Anna C. Ferrari, M.D. 
New York University Cancer Institute 
160 East 34th St, 8th Floor 
New York, NY 10016 
Phone: 212-731-5389 
Fax: 212-731-5545 
Email: anna.ferrari@nyumc.org 
 
Ron Rodriguez, M.D. 
University of Texas Health Science Center at 
San Antonio 
Department of Urology 
7703 Floyd Curl Drive, MC7845 
San Antonio, TX 78229-3900 
Phone: 210-567-5643 
Fax: 210-567-6868 
Email: rrodriguez@jhmi.edu 
 
STUDY CHAIR LIAISON (SCL) 
 
Samantha Davis 
Clinical Trials Office of New York University 
Cancer Institute 
1 Park Avenue, Mezzanine 
New York, NY 10016 
Phone: 212-263-4406 
Fax: 212-263-4477 
Email: samantha.davis2@nyumc.org 
 
 
 
 
 
Rev. 4/12, 7/13 
Rev. 2/13 

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Schema 
R
A
N
D
O
M
I
Z
E
Accrual Goal = 104
Cycle Length = 28 days
Stratify:
· Gleason score: 
· ≤ 6
· 7
· 8 to 10 
· Prior hormonal 
therapy
· Yes
· No
Arm B
Cycles 1-3 (Weeks 1-12)3, 4: 
MK-2206 200 mg once per week, orally1, 3
Cycles 4-11 (Weeks 13-44)2: 
Bicalutamide (Casodex) 50 mg/daily, 
orally and continue MK-2206 200 mg once 
per week, orally
Arm A
Cycles 1-3 (Weeks 1-12): Observation 
without treatment
Cycles 4-11 (Weeks 13-44)2: Bicalutamide 
(Casodex) 50 mg/daily, orally, 
continuously to end of study
P
S
A
E
V
A
L
U
A
T
I
O
N
Monthly
1. MK-2206 should be taken at approximately the same time each week 2 hours before or after meals.
2. Patients on Arm A and Arm B who are responding at Cycle 11 (week 44)  may continue on until Cycle 18 (week 72) at the investigator’s 
discretion. (See Section 5.6).
3. Patients with PSA < 0.2 by the end of Cycle 3 (Week 12) will NOT receive bicalutamide until the PSA rises ≥ 0.2 ng/mL and the rise is 
confirmed on a second determination 2 weeks later. 
4. Patients with a PSA rise of ≥ 50% above baseline may start bicalutamide early.
 

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1. 
Introduction 
1.1 
Prostate Cancer 
Around 25-30% of prostate cancer (PC) patients experience Prostate Specific 
Antigen (PSA) recurrence (~60,000 cases/year) after primary therapy (1,2), 
which precedes the development of clinical metastasis by months or years (3).  
Androgen deprivation therapy (ADT) is the only treatment modality currently 
available for recurrent PC. However, it is not curative (4) and exerts a selective 
pressure for survival and growth of preexisting androgen-independent clones (5) 
that drive castration resistant progression. In addition to negative impact in 
quality of life (QOL), ADT increases metabolic and cardiac morbidity that can 
compromise survival (6-8). Therefore, new treatment modalities to improve or 
substitute ADT are needed. 
1.2 
Androgen Receptor in Prostate Cancer 
The evidence from human and experimental model systems indicates that the 
androgen receptor (AR) plays a pivotal role in supporting PC development (9-11) 
and progression in the androgen-dependent (AD) and androgen-independent (AI) 
stages of the disease (12-14). 
AR is a member of the steroid receptor super family. Dihydrotestosterone (DHT) 
generated intracellularly by 5-alpha reductase from testosterone is the ligand with 
the highest affinity and specificity for the ligand binding domain (LBD) in the C-
terminus of AR. Liganded AR is transferred to the nucleus where it binds to 
androgen-responsive elements (ARE) in the promoter of target genes and 
recruits co-activators and co-repressors to regulate their transcription. AR 
controls expression of a wide spectrum of genes involved in proliferation, 
differentiation, survival and metabolism (15).   
AR over-expression and activation are among the most consistent findings in 
human tumor xenografts (16) and the dominant molecular pathway activated 
during emergence of castration resistant clones (17). AR over-expression is 
frequent in both localized (18) and metastatic tissues (19,20) of PC patients and 
has been linked to higher clinical stage and earlier relapses (16).  Importantly, 
strategies to reduce AR levels of expression by either molecular silencing or by 
treatment with histone deacetylase inhibitors (HDACI) indicated that both, the 
androgen-dependent growth and the apoptosis response to biological and 
chemotherapeutic agents could be restored in androgen-independent LNCaP 
cells resistant to these treatments (21-24).  Therefore, a clinical trial to test the 
effect of HDAC on restoration of hormone sensitivity is under way. 
The regulation of AR transcriptional activation of downstream target genes can 
be initiated by ligand-dependent and ligand-independent mechanisms (25).  
Ligand-dependent activation is the predominant pathway in normal and 
androgen-dependent PC cells. In the castrate environment it is sustained in part 
by over-expression and mutations of AR that exploit multiple mechanisms (26) 
including  AR hypersensitivity to very low intracellular levels of androgens (27), 
and promiscuity for binding other steroid hormones such as estradiol and 
progesterone (28).  In addition, PC cells develop mechanism to synthesize their 
own androgens by increasing the expression of genes that convert adrenal 

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androgens to testosterone (29) and by up-regulating steroidogenic enzymes that 
metabolize cholesterol to DHT (30,31). Therefore, the ligand-dependent pathway 
of AR activation remains active under castration-resistant conditions. 
Non-steroidal anti-androgens are direct antagonist of AR. As such, bicalutamide 
regulates AR function by competing for agonists binding to the LBD, by 
decreasing AR phosphorylation by various growth factors (32) and by preventing 
recruitment to the ARE's of co-activators to initiate transcription of target genes 
(33-35). New generation anti-androgens such as MDV3100 also work by 
decreasing the nuclear localization of AR (34). In the clinic, anti-androgens have 
shown promising results in non-castrate and castration resistant PC patients 
(34,36-38).  
Ligand-independent activation of AR stems from two different mechanisms: 1. 
Increased cross-talk of AR with intracellular second messengers of cell 
membrane growth factor receptors (GFR) and their ligands activated by autocrine 
and paracrine mechanisms that evolve during PC progression. These include 
among many others the epidermal growth factors/receptors (EGF/R, HER2), 
insulin-like growth factor/receptor (IGF/R) (39,40) and interleukin-6 (IL6) (35,41-
43) which signal through networks of protein kinases (PKs) including 
PI3K/PTEN/AKT/mTor, Ras-Raf-MEK-ERK, Src/JAK /STAT. These relay 
downstream signals that directly or indirectly through their substrates 
phosphorylate and activate AR (44-47). 2. Androgen receptor splicing. A number 
of different AR splice variants (SV) were recently identified in castration resistant 
cell lines, in xenografts models (48) and tissues from PC patients (49,50). A 
common pattern of the SV is the loss of the LBD of AR with retention of the N 
terminus and 2 or 3 zinc fingers for DNA binding.  The SV can translocate to the 
nucleus, bind to ARE's and regulate the expression of AR target and non target 
genes involved in diverse cellular functions. There is also evidence that SV can 
activate AKT-1 in PTEN positive PC cells and phosphorylate both AR wild type 
and SV's (50). Therefore, SV's are constitutively active and by lacking LBD are 
not inhibited by anti-androgens. Although the expression of the SV in PC cells is 
less abundant than wild type AR, it is thought that in the setting of castration they 
may hijack the wild type AR to regulate genes transcription (49,50). Thus, AR 
splicing provides yet another mechanism to escape androgen deprivation and 
support AI progression. 
1.3 
The PI3K/PTEN/AKT/mTor pathway  
The PI3K/PTEN/AKT/mTor pathway is central to the transmission of growth 
regulatory signals from cell surface receptors. In brief, (51,52), upon activation of 
receptors by ligand binding, PI3K forms heterodimers comprised of a regulatory 
subunit (p85) and a catalytic subunit (p110) and serves as a docking site for 
AKT. The function of PI3K is tightly controlled and inactivated by the tumor 
suppressor PTEN, a dual specificity phosphatase whose expression is frequently 
lost in cancer (52,53).  AKT is a serine-threonine kinase that once localized to the 
plasma membrane is phosphorylated and activated at threonine 308 by PDK-1 or 
at serine 473 by the mTor/Rictor complex. AKT is the central mediator of the 
PI3K activation cascade and affects multiple cellular functions that contribute to 
cancer: A. Stimulates protein synthesis and cell growth through the TSC 1/2 
complex and its activation of the mTor/Raptor complex which affects glycolysis 
and angiogenesis by stabilizing insulin and Hif1alpha response to hypoxia (54);  
B. Induces proliferation by facilitating progression along the G1-S cell cycle 

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check point through inactivation of the cell cycle inhibitors p27 and p21 and by 
activating the forkhead box trancription factors (FOXO) and GSK3 which induces 
c-Myc and Cyclin D 1; C. Supports cell survival by limiting programmed cell death 
through inhibition of pro-apoptotic genes like Fas ligand, Bim and BAD and by 
promoting p53 degradation and deregulation of NFkB function. D. Deregulates 
glucose metabolism and insulin signaling by enhancing glucose uptake and 
glycogen synthesis in muscle and fat and by inhibiting of gluconeogenesis in the 
liver. mTor has two forms and complexes: the mTORC1-Raptor-mLST8 complex 
which controls protein synthesis and growth is Rapamycin sensitive. The 
mTORC2 Rictor -mLST8 complex, that phosphorylates AKT at Ser 473 and is 
Rapamycin insensitive. Therefore, Rapamycin analogues have clinical activity 
(55) that has been limited by the phosphorylation of AKT through the mTORC2-
Rictor complex that results in induction of cyclin D1 and c-Myc through GSK3 
(56) and also through activation of MAPK by a PI3K-dependent feedback loop 
(57).   
The PI3K/PTEN/AKT/mTor pathway is frequently deregulated in prostate cancer 
and enhances AR activation. Multiple lines of evidence implicate decreased 
expression of PTEN and increased expression of PI3K, AKT and mTor  in the 
development and  progression of PC (58-60). Loss of PTEN expression through 
epigenetic silencing, deletions or mutations was observed in 15-63% of radical 
prostatectomies and correlated with high Gleason score, advanced stage and 
poor clinical outcome (59,61,62). It was also observed in 39-70% of castration 
resistant specimens (63,64). Amplfication of PI3K was detected in 39% of 
localized specimens and in 50% of castration resistant PC (65). Activation of 
AKT-1 has been detected primarily in cases with loss of PTEN (66). However, in 
a recent study of 400 radical prostatectomy specimens that quantified AKT-1 
expression by fluorescence microscopy, expression of AKT-1 was detected in 
81,75% and 73% had high levels of expression. Among those with high levels of 
AKT-1 there was a significant correlation with high Gleason scores, advanced 
stage, increased risk of biochemical recurrence and prostate specific mortality 
(67-69).  Biologically, AKT activation has been shown to increase AR expression 
and activity in both normal and tumor epithelial cells (70), to accelerate 
androgen-independent progression (60) and development of resistance to 
hormone therapy (44).  In the castrate environment, AKT phosphorylates the N-
terminus and LBD of AR (71,72), decreases AR degradation (73) and sustains 
AR transcriptional activity and growth of PC cells at low androgen levels (74,75). 
It's been recently suggested that AKT activation can also provide an escape 
pathway to direct AR silencing (76). Activation of mTOR and/or Sk6 was also 
found to be increased in 12,5 and 26,5% respectively of intermediate-risk and 32 
and 69% of high-risk localized PC specimens (77). In addition to the loss of 
PTEN and activation of AKT, androgens have been shown to activate mTor to 
promote PC cell proliferation through post-transcriptional increases in cyclin D 
(78). In the clinic, the response to Rapamycin or Temserolimus of castration 
resistant patients with PTEN deficiencies was modest (79,80) suggesting that 
release of mTORC-2 and PI3K provides a mechanism of escape and dual 
inhibitors or direct inhibition of AKT may be more effective. 
It is apparent from the experimental and human data presented above that the 
PI3K/PTEN/AKT/mTor pathway in androgen-dependent and -independent PC 
cells supports a more stable and "hypersensitive" AR protein that facilitates the 

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recruitment of transcriptional co-activators to the ARE's and activation of growth 
and survival genes in the presence or absence of androgens (60,81-83). 
In summary, there is a strong rationale for considering the AR as a therapeutic 
target in recurrent, non-castrate PC. Both experimental and human data suggest 
that PC cells have an "addiction" to AR activity. It is apparent that the AR 
facilitates the growth and survival of PC cells by responding to signals from 
androgens, other steroid hormones and multiple kinases whose activity becomes 
altered during PC progression.  These molecules sustain AR levels and 
activation by increasing phosphorylation and protein stability or by serving as co-
activators of transcription. In concert, they establish a vicious cycle that supports 
androgen-independent progression. Although activation of AR and its 
transcriptional activity by intracellular second messengers does not require 
ligand, ligand-binding facilitates the process and remains active throughout all 
stages of PC. Therefore, blocking the LBD remains crucial to block the androgen 
pathway of activation.  
The availability of PK inhibitors, and effective anti-androgens provides the means 
to test novel therapeutic strategies aimed at the AR to control recurrent PC 
progression. Given the palliative nature and unfavorable toxicity profile of 
castration, a testosterone-sparing option with the potential to improve QOL and 
outcome is highly desirable for patients with rising PSA levels after primary 
therapy. 
Preclinical evidence of antitumor activity of single PI3K/AKT/mTor 
inhibitors in PC models  
Treatment of an androgen-dependent PC xenografts with a humanized IGF1R 
monoclonal antibody decreased AKT phosphorylation and induced extensive 
apoptosis that reached 60% tumor volume reduction. The effect was less 
pronounced in an androgen-independent derivative but became synergistic in 
combination with docetaxel (84). Treatment of androgen-dependent LNCaP cells 
and an androgen-independent derivative with MK-2206, the inhibitor of PKC, 
GSK3β and ribosomal protein S, reduced AR mRNA and protein levels, 
decreased tumor growth and induced apoptosis (85). Treatment of androgen-
dependent and independent LNCaP cells with the MAPK inhibitor PD98059 and 
the mTor  inhibitor Rapamycin did not affect AR levels but induced growth arrest 
without apoptosis (81,86,87).  
Combinations of anti-androgen with PI3K/AKT/mTor or HDAC inhibitors 
In vitro studies of androgen-dependent and -independent LNCaP cells showed 
the combination of bicalutamide with rapamycin was synergistic while the 
combination with an EGFR inhibitor (Iressa) was additive (88,89). The 
combination of bicalutamide with the HDAC inhibitors (SAHA and LBH589 ) was 
also synergistic and induced apoptosis that was more pronounced in androgen-
independent LNCaP cells resistant to bicalutamide [24]. Treatment of androgen-
independent LNCAP cells with the novel anti-androgen VN/124 in combination 
with an mTor inhibitor was also synergistic while the combination with the EGFR 
inhibitor (Gefitinib) was additive (90).  
In vivo studies in a PTEN deficient xenografts model that is androgen-dependent, 
expresses AR and has an activated AKT/ mTor pathway showed that both 
casodex and castration had a similar effect on tumor volume reduction and 

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became additive in combination with rapamycin. While castration and casodex 
reduced AR levels and decreased proliferation they did not increase caspase 
activation and had no affect on mTor activation. In contrast, rapamycin inhibited 
S6RP but did not affect AR. The combination of casodex and rapamycin showed 
a pronounced decrease in proliferation markers (91). Unpublished data 
developed by Merck investigators with MK-2206 showed in the same PTEN 
knockout model that the growth inhibition in response to MK-2206 was more 
pronounced than casodex and the combination was strongly synergistic. Neither 
casodex or ADT affected phosphorylation of AKT. 
In summary, the in vivo model confirms previous in vitro studies in androgen-
dependent and independent LNCaP PC cells indicating that a combined 
approach to block the AR LBD with an antiandrogen and the ligand-independent 
pathway with inhibitors of AKT/mTor pathway has potential to enhance tumor 
responses. This approach might be most effective in patients with recurrent PC 
at high risk of progression since AR over-expression, loss of PTEN and AKT 
activation are frequent, and 2/3 of these patients are at increased risk of relapse 
and death form PC. Furthermore, AKT inhibitors may also serve to block the 
activity of AR splice variants that evade anti-androgen block. 
1.4 
Clinical Experience with Non-Castrating Peripheral Androgen Blockade 
Strategies 
Peripheral androgen blockade strategies using monotherapy with a nonsteroidal 
anti-androgen or in combination with finasteride to block 5-alpha reductase and 
the conversion of testosterone to DHT were developed to avoid the side effects 
of androgen ablation and to improve QOL. 
In the early 1990’s, phase II and III trials with bicalutamide 50 mg was tested as 
monotherapy in metastatic D2 patients with high PSA levels. By 3 months, 20% 
of patients had a PSA decline of 85%, and by 6 months, 40% of the patients 
reached a 90% decline. Those who achieved this response had longer survival 
but was inferior to castration. This approach was never tested in rising PSA non-
castrate patients (92-95). Instead, bicalutamide150 mg (96) was compared to 
combined androgen suppression with orchiectomy or LHRH agonist (Zoladex) 
and flutamide (Eulexin) in patients with locally advanced PC. At 6.3 years follow-
up there was no statistical difference between the two groups in time to 
progression or overall survival (56% mortality). In the bicalutamide arm there was 
a significant improvement in QOL due to improved physical capacity, emotional 
well being and sexual interest (97).  In a smaller study in more advanced patients 
with median PSA values at study entry of 19.1 ng/mL, the addition of finasteride 
after bicalutamide 150 mg induced a secondary PSA nadir suggesting PSA 
levels did not become undetectable and finasteride was needed to provide 
additional intracellular androgen blockade. At a follow up of 3.9 years, disease 
control was comparable to castration. However, undetectable PSA levels were 
not reported (98). 
A more recent study by Picus, et al, (99) used a similar combination to treat 101 
androgen-dependent non metastatic PC patients (D0) with rising PSA >1 and 
<10 ng/mL after primary therapy. From the median PSA at registration of 3.8 
ng/mL, 97% (95/98) reached a PSA <1 ng/mL (>80% PSA decline) at a median 
of 3.2 months and 77% achieved an undetectable PSA (<0.2 ng/mL) at a median 
of 5.5 months that lasted several months (33 months). At 59 months, the median 

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time to progression (PSA>4 ng/mL or 50% above nadir) had not been reached 
with 47(46%) patients still on the same combination. There were 22 (33%) 
patients that experienced PSA failure and 15 patients responded to subsequent 
androgen deprivation.  Eight patients died of unrelated causes and 22 went off 
therapy unrelated to progression. Toxicity was very low.  
In a small phase II study of D2 patients with eulexin followed by the addition of 
finasteride (100), the median PSA decline on eulexin was 87% at a median of 9.1 
weeks. After adding finasteride, the median PSA decline reached 94% at 16.5 
weeks and 40% reached undetectable levels.  
1.5 
Nadir PSA Response to Castration and Outcome 
In a retrospective analysis of 747 patients with biochemical recurrence and 
negative bone scan after surgery or radiation, a nadir PSA level <0.2 ng/mL at 8 
months after hormonal therapy was, in multivariate analysis, an independent 
prognostic factor of PC-specific mortality compared to other known prognostic 
factors such as PSA doubling time (PSADT) <3 months, PSA level at the start of 
androgen deprivation and Gleason score 8-10. PSA nadir >0.2 accounted for 
75% of the cancer deaths observed in the study (101). A retrospective analysis of 
130 patients treated with androgen ablation for rising PSA also found that 31 
(57%) of 54 (95% confidence interval 44% to 71%) patients with a rising PSA 
level alone and 28 (37%) of 76 (95% confidence interval 26% to 47%) with a 
rising PSA and clinical metastases achieved an undetectable PSA after 
androgen ablation (P = 0.02). The PSA level at the start of androgen ablation and 
the presence of metastases were the most significant predictive factors (102). 
The PSA nadir after neoadjuvant therapy was also a predictor of organ-confined 
disease and outcome (103). In metastatic D2 patients, the absolute PSA value 
after androgen deprivation was also a strong independent predictor of survival 
(104). In this study, at 7 months of initiation of androgen deprivation, patients 
who achieved a nadir PSA below 4 ng/ ml had less than half the risk of death 
than those that did not reach that nadir and those that achieved undetectable 
PSA levels had a quarter the risk than those that did not reach that nadir 
(p=<0.001 respectively). Therefore, a detectable PSA following castration reflects 
the surviving, prognostically relevant tumor cell population. 
Conclusion: the existing retrospective data supports that in non-castrate patients 
starting androgen deprivation achieving an undetectable PSA nadir (<0.2 ng/mL) 
predicts for a longer survival than those whose PSA remains detectable. Thus, 
an undetectable PSA nadir promises to be the only accurate measure of disease 
response and an important endpoint for clinical trials evaluating new approaches 
in hormone naïve PC patients. However, PSA declines ≥85% may also be 
considered to explore the activity of novel androgen-sparing combinations in a 
similar group and time frame. Combined peripheral androgen blockade regimens 
induced an undetectable (<0.2 ng/mL) PSA in 40-77% of patients depending on 
whether the PSA levels at study entry were above or below 10ng/mL respectively 
and, achieved the nadir in 4-6 months. Based on this limited data, combined 
androgen-sparing regimens with high level of activity as proposed here can be 
expected to induce undetectable PSA by 8 months in 45% of patients whose 
PSA level at study entry is not restricted to <10 ng/mL and have a PSADT less 
than 12 months. In this group, only 20% may achieve a PSA nadir <0.2 with 
antiandrogen monotherapy.  

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1.6 
Molecular Features and Response to Therapy 
The experience with targeted therapy in solid tumors indicates that clinical 
responses are dependent on dominant molecular alterations of the target(s) as a 
result of their aberrant expression and/or mutations (105). Prostate cancer is a 
genetically complex and highly heterogeneous tumor with considerable variability 
in the level of AR expression and PK activation (106). We predict that the ability 
of the combination to down-regulate AR levels and PSA will be influenced by the 
genetic make up of the PC in each patient and account for differences in 
response across patients in the same therapeutic arm. Accurate prediction of the 
drug's effect requires a thorough knowledge of all the genes (and gene variants), 
microRNA's and proteins involved in the etiology of the disease and the drug’s 
mode of action and metabolism. Therefore, analysis of primary tumor tissues will 
be important to determine the preexisting levels of expression and alterations of 
AR and relevant targets in the pathway of MK-2206 (i.e. PTEN, phopho AKT, 
GSK-3b, etc), and to establish their relation to clinical response.  In addition, new 
markers and micro RNA's detected in serum of PC patients (107) have been 
correlated to the presence of PC in patients independent of PSA levels and need 
to be further explored in the setting of rising PSA. For these reasons we will 
request permission to retrieve and bank samples of the original tumor specimens 
for later molecular analysis. 
1.7 
Rationale and Hypothesis 
Hypothesis: We postulate that a global strategy to modulate AR activation 
without testosterone deprivation can be implemented to successfully prevent the 
progression of androgen-dependent and preexisting androgen-independent 
clones in patients with recurrent PC at high-risk of progression. We propose 
utilizing combinations of agents to simultaneously block the AR LBD with 
antiandrogens and the cross-talk with activated PKs using specific inhibitors or 
agents that decrease the levels of AR expression. We predict that this combined 
approach will reduce expression and function of AR in PC and target tissues that 
will reduce PSA to undetectable levels. We expect a marked antitumor response 
with a prolonged period of remission or cure. By preserving testosterone, we 
expect patients to experience a better QOL compared to historical controls 
treated with androgen deprivation. Furthermore, in cases of progression, we 
predict that the recurrent tumor in a non-castrate environment will remain 
androgen-sensitive and responsive to androgen ablation. Finally, we predict that 
this prolonged hormone sensitive state will be associated with increased survival. 
1.8 
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, AKT plays a 
pivotal role in rendering tumor cells insensitive or resistant to chemotherapy or 
targeted agents. 

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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-2006 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 
proteins including kinases without demonstrating significant (≥50%) inhibition 
against any protein. 
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 27 cell lines were insensitive (IC50>5 mcM) to MK-2206.  
Highly sensitive cell lines included breast, ovarian, prostate, 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 

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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 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 

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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 
Specie 
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-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 
Rev. 4/12 

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(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.   
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 

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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 either 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 mM•h and 62.2 nM, respectively, for 60 mg QOD, and 14.8 mM•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.   
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 

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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.   
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.   

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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. MK-
2206 was shown to be a P-gp substrate. 
MK-2206 Dose selection:  
The 200 mg PO on the QW schedule of MK-2206 was chosen to be used in 
combination with bicalutamide for the following reasons: 
· 
the 200 mg dose reached a mean Cmax of  170 nM (after the first dose) and 
a Cmax of ~225 nM (SS).  The PK targetof 60 nM was achieved with a C12 
hours in 99.9% and C24 hours in 92.8 % of  the patients. The mean coverage 
above target PK was 133 hours out of 168 hours.  
· 
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. 
· 
The QW has been generally well-tolerated. Severe skin rash was observed in 
16.7% compared 11.9% at the dose of 60 mg QOD. Hyperglycemia was not 
observed. 
· 
Although too early, PSA stabilization was observed in CRPC patients at the 
90 and 200 mg QW. 
1.9 
Selection Criteria 
The criteria to select patients with biochemical recurrence (D0) as the only 
manifestation of disease progression after definitive local therapy was based on 
parameters identified to be best predictors of outcome in long term studies of this 
group of patients.  D0 patients at high-risk of progression and PC-related death 
included those with a PSA doubling time (PSADT) of < 12 months or a time to 
PSA rise of < 3 years from surgery or a Gleason score 8-10. However, in 
practical terms, it is generally accepted that the PSADT is the best marker and 
tends to occur in those with a high Gleason score (108-113). In these cases, the 
potential benefits would likely outweigh the side effects of investigational agents 
and the benefits of a successful intervention should be more readily apparent 
since they have a shorter time to progression. We also considered the fact that 
there are spontaneous fluctuations in PSA levels in non-castrate patients and 
that these could affect the evaluation of PSA change in response to novel 
therapeutic interventions. Therefore, from weeks 1-12 weeks of the study we will 
measure PSA changes as a result of spontaneous fluctuations in the control arm 
A and under the effect of the MK-2206 alone in arm B. A 12 week period is safe 
and adequate to measure sequential PSA levels and will increase our ability to 
detect smaller, nonrandom effects of MK-2206 on serum PSA.  If treatment with 

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20 
MK-2206 does not translate into a PSA decline beyond spontaneous fluctuations 
it does not exclude the potential synergy with bicalutamide. Therefore, unless 
there is clear evidence of disease progression, patients on both arms will 
proceed to the second phase of the treatment. In the setting of normal androgen 
levels, MK-2206 alone is unlikely to induce PSA declines to the extent expected 
with bicalutamide. We may be able to assess this difference by the PSA 
response observed from weeks 13-44 in patients treated with bicalutamide in arm 
A. 
To have a real-time assessment of the PSA response to antiandrogen 
monotherapy in patients with a PSADT<12 months and to evaluate the potential 
added benefit of MK-2206, we will measure sequential PSA levels for a period of 
32 weeks, weeks 13-44, the effect of bicalutamide in patients randomized to arm 
A and the potential benefit of adding MK-2206 to bicalutamide in patients 
randomized to arm B. We chose 8 months of antiandrogen monotherapy or 
combined therapy as a cut point to asses response, because it was the duration 
of treatment required to achieve maximum PSA response to castration and to 
have prognostic implications (101,102). Thus, if the combination is more active 
than single agent, more patients treated in arm B should reach undetectable 
PSA.  
This study design, using bicalutamide as a backbone, may serve to sequentially 
evaluate the activity of various targeted agents/combinations in the Rising PSA 
non-castrate patient population   
In summary, during the initial 3 months on study, we will determine the effect of 
MK-2206 on PSA compared to spontaneous variations. In the subsequent 8 
months of study, we will evaluate the effect on PSA decline of MK-2206-
bicalutamide compared with bicalutamide alone, by the proportion of patients that 
achieve an undetectable PSA (<0.2 ng/mL) in both arms. We estimate 20% of 
patients in the control group will reach undetectable PSA and this will increase to 
45% in the MK-2206-bicalutamide group.  
1.10 
Gender and Ethnicity  
Study entry is open to male patients of all ethnic backgrounds. In recent ECOG 
Phase II trials, approximately 11% of patients were non-Caucasian. Given the 
limited size of the patient population to be accrued on these regimens, there will 
be limited power to determine differences in toxicity or efficacy between racial 
groups. However, we will describe any apparent differences observed in toxicity 
or efficacy. 

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2. 
Objectives 
2.1 
Primary 
2.1.1 
To compare the two regimens on the proportion of patients with 
undetectable PSA level (< 0.2 ng/mL) at 44 weeks. 
2.2 
Secondary 
2.2.1 
To assess the proportion of patients with PSA decline > 85% at 44 
weeks on the combination therapy arm compared to that of 
bicalutamide monotherapy arm. 
2.2.2 
To assess the distribution of best PSA response in each study arm.  
2.2.3 
To assess the time to PSA progression in each arm of the study. 
2.2.4 
To assess the time to PSA nadir in each arm of the study. 
2.2.5 
To assess the duration of PSA response in each arm of the study. 
2.2.6 
To characterize the PSA slope pre-study, during treatment, and off 
treatment. 
2.2.7 
To evaluate the safety and tolerability of MK-2206 in this patient 
population. 
2.2.8 
To determine whether Gleason score has any effect on PSA response 
to treatment. 
2.2.9 
To determine whether prior hormonal therapy has any effect on PSA 
response to treatment. 
2.3 
Laboratory Studies Objectives 
Samples of the primary tumor specimen will be retrieved for banking and future 
analysis of the molecular profile of the primary PC tissues with emphasis on the 
AR and Akt upstream and downstream signaling pathways. 

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3. 
Selection of Patients 
Each of the criteria in the checklist that follows must be met in order for a patient to be 
considered eligible for this study. Use the checklist to confirm a patient’s eligibility. For 
each patient, this checklist must be photocopied, completed and maintained in the 
patient’s chart.  
In calculating days of tests and measurements, the day a test or measurement is 
done is considered Day 0. Therefore, if a test is done on a Monday, the Monday 
four weeks later would be considered Day 28.  
ECOG-ACRIN Patient No. ____________________________ 
Patient’s Initials (L, F) _______________________ 
NOTE: 
All questions regarding eligibility should be directed to the Study Chair or 
Study Chair Liaison. 
NOTE: 
Institutions may use the eligibility checklist as source documentation if it has 
been reviewed, signed, and dated prior to randomization by the treating 
physician. 
3.1 
Eligibility Criteria 
3.1.1 
Patient must be at least 18 years of age. 
3.1.2 
Patient must have histologically confirmed diagnosis of prostate 
cancer. 
3.1.3 
Patient must have had previous treatment with definitive surgery or 
radiation therapy or cryoablation. 
3.1.4 
Patient may have prior salvage therapy (surgery, radiation or other 
local ablative procedures) within 4 weeks prior to randomization if the 
intent was for cure. Prophylactic radiotherapy to prevent 
gynecomastia within 4 weeks prior to randomization is allowed. 
3.1.5 
Patient must have no evidence of metastatic disease on physical 
exam, CT abdomen/pelvis (or MRI), chest x-ray (or CT chest) and 
bone scan within 8 weeks prior to randomization. 
Study:______________ Date:______________ 
3.1.6 
Patient may have had prior neoadjuvant and/or adjuvant therapy 
(chemotherapy, vaccines or experimental agents) within 4 weeks prior 
to randomization, if the PSA rise and PSADT were documented after 
the testosterone level was > 150 ng/dL. 
Date prior neoadjuvant and/or adjuvant therapy stopped:________ 
3.1.7 
Patient may not have had therapy modulating testosterone levels 
(such as luteinizing-hormone, releasing-hormone agonists/antagonists 
and antiandrogens) within 1 year prior to randomization, unless it was 
in the neoadjuvant and/or adjuvant setting. 
Agents such as 5 alpha reductase inhibitors, ketoconazole, 
abiraterone, systemic steroids, or herbal supplements known to 
decrease PSA levels including any dose of Megestrol acetate, 
_____
_____
_____
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Finasteride (e.g., Saw Palmetto and PC-SPES, African pygeum 
extract, lycopene, alanine, glutamic acid and glycine, beta-sitosterol, 
lycopene, nettle root extract, quercitin, Belizian Man Vine extract, 
mulra puama extract and epimedium extract Campesterol, Beta-
sitosterol, Stigmasterol, Sitostanol and Brassicasterol) are not 
permitted at any time during the period that the PSA values are being 
collected. 
3.1.8 
Patient must have hormone-sensitive prostate cancer as evident by a 
serum total testosterone level > 150 ng/dL within 12 weeks prior to 
randomization. 
Serum total testosterone level: _________ Date of test:__________ 
3.1.9 
Patient must have evidence of biochemical failure after primary 
therapy and subsequent progression. 
Biochemical failure is declared when the PSA reaches a threshold 
value after primary treatment and it differs for radical prostatectomy or 
radiation therapy. 
For radical prostatectomy the threshold for this study is PSA ≥ 0.4 
ng/mL  
For radiation therapy the threshold is a PSA rise of 2 ng/mL above the 
nadir PSA achieved post radiation with or without hormone therapy 
(2006 RTGO-ASTRO Consensus definition). 
PSA progression requires a PSA rise above the threshold (PSA1) 
measured at any time point since the threshold was reached.  
The PSADT must be <12 months; requires two consecutive PSA rises 
(PSA2 and PSA3) above the PSA1; PSA2 and PSA3 must be 
obtained within 6 months of study entry. All baseline PSAs should be 
obtained, preferably, at the same reference lab. 
3.1.10 
PSADT calculation needs 3 PSA values: 
PSA1:__________ Date:________ is any PSA value that is equal or 
greater than the threshold PSA (0.4 ng/mL for radical prostatectomy 
or 2 ng/mL above the nadir for primary radiation therapy) indicating 
biochemical relapse. 
PSA2:__________ Date:________must be higher than PSA1, 
obtained at least 2 weeks after PSA1 and within 6 months or less from 
randomization 
PSA3:__________ Date:________must be higher than PSA2 and 
obtained at least 2 weeks after PSA2  
Baseline PSA _____Date:_____must have reached a minimum of 2 
ng/mL but be no greater than 50ng/mL and equal or higher than 
PSA3. PSA3 may be used as baseline PSA if obtained within 1 week 
of randomization 
_____
_____
Rev. 4/12 
Rev. 4/12, 
       9/12 
______
Rev. 2/13 

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3.1.11 
Patient's PSA doubling time (PSADT) must be less than 12 months, 
calculated using the following formula: 
PSADT in 
days 
= 
0.693 (t) 
In (PSA3) – In (PSA2) 
Where t = the number of days between PSA3 and PSA2 
In = the natural log 
PSADT in months = PSADT in days divided by 30.4375 
3.1.12 
Patient must have an ECOG Performance Status of 0 or 1. 
3.1.13 
Patient must have adequate end-organ function as evident by the 
following lab values obtained within 4 weeks prior to randomization: 
3.1.13.1 
Granulocytes ≥ 1500/mm3 
3.1.13.2 
Granulocytes: _______ Date of test: __________ 
3.1.13.3 
Platelet count ≥ 100,000/mm3 
3.1.13.4 
Platelet count: _______ Date of test: __________ 
3.1.13.5 
Serum creatinine within normal institutional limits or 
creatinine clearance ≥ 50 ml/min for patients with 
creatinine levels above institutional normal. 
Creatinine: _____ ULN: _____  
Creatinine Clearance: _____ Date of test: _____ 
3.1.13.6 
Serum total bilirubin  1.5 times the upper limit of normal 
(ULN), and alkaline phosphatase (ALP)  2.5  ULN  
Serum total bilirubin:__________   
ULN:_______ Date of test:_______ 
Alkaline phosphatase:_________   
ULN:_______ Date of test:_______ 
3.1.13.7 
SGOT (AST) and SGPT (ALT) < 2.5 x institutional upper 
limit of normal. 
SGOT (AST): _______ 
ULN:_______  Date of test: __________ 
SGPT (ALT): _______ 
ULN:_______  Date of test: __________ 
3.1.14 
HIV-positive patients are excluded from this study because of possible 
pharmacokinetic interactions with MK-2206.  
3.1.15 
Patient cannot receive concurrent therapeutic administration of 
anticoagulant therapy. Low dosage aspirin ≤ 325 mg per day is 
allowed 
_____
_____
_____
_____
_____
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3.1.16 
Patients with impaired cardiac function including any one of the 
following will be excluded from entry on study: 
· 
Baseline QTc > 450 msec (male) (Patients with QTc 450-480 
msec will be allowed to participate in this trial if they do not have 
any of the other cardiac conditions mentioned in this section). A 
list of medications that may cause QTc interval prolongation are 
listed in Appendix VII, and should be avoided by patients entering 
on trial.  
· 
Patients with congenital long QT syndrome 
· 
History of sustained ventricular tachycardia 
· 
Any history of ventricular fibrillation or torsades de pointes 
· 
Concomitant use of drugs with a risk of causing torsades de 
pointes 
· 
Bracardia defined as heart rate < 50 beats per minute.  Patients 
with a pacemaker and heart rate ≥ 50 beats per minute are 
eligible. 
· 
Myocardial infarction or unstable angina within 6 months of study 
entry  
· 
Congestive heart failure (NY Heart Association class III or IV)  
· 
Right bundle branch block and left anterior hemi-block (bifasicular 
block) 
3.1.17 
Patient must not have GI tract disease resulting in an inability to take 
oral medication, malabsorption syndrome, a requirement for IV 
alimentation, prior surgical procedures affecting absorption, 
uncontrolled inflammatory GI disease (e.g., Crohn’s, ulcerative colitis). 
3.1.18 
Patient may not be receiving any other investigational agents or 
receiving concurrent anticancer therapy (chemotherapy, 
immunotherapy, radiation therapy, surgery for cancer, or experimental 
medications) at time of randomization.   
3.1.19 
Patient may not have a history of allergic reactions attributed to 
compounds of similar chemical or biologic composition to MK-2206 or 
bicalutamide. 
3.1.20 
Patient must not have any uncontrolled intercurrent illness including, 
but not limited to, ongoing or active infection, cardiac arrhythmia, or 
psychiatric illness/social situations that would limit compliance with 
study requirements. 
3.1.21 
Patients with diabetes or at risk for hyperglycemia MUST not be 
excluded from trials with MK-2206, but the hyperglycemia should be 
well controlled before the patient enters the trial. Please follow Section 
5.4.4 for glucose monitoring during study for this patient population. 
3.1.22 
Patients receiving any medications or substances that are 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 VI. 
_____
_____
_____
_____
_____
_____
_____
Rev. 4/12 
Rev. 2/13 
Rev. 6/13 
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3.1.23 
Patient must NOT have previous or concurrent malignancy. 
Exceptions are made for patients who meet any of the following 
conditions: 
· 
Basal cell or squamous cell carcinoma of the skin 
OR 
· 
Prior malignancy has been adequately treated and patient has 
been continuously disease free for ≥ 2 years. 
Date of last evidence disease:___________ 
3.1.24 
The effect of the study medications on the developing human fetus 
are unknown. For this reason, patient must agree to use barrier 
contraception during and for 3 months after discontinuation of study 
treatment. If patient impregnates a woman while on treatment or 
within 3 months of discontinuing treatment, he should inform his 
treating physician immediately. 
3.1.25 
Patients must discontinue use of enzyme-inducing anti-epileptic drugs 
(EIAEDs)  14 days prior to study enrollment.  The investigator may 
prescribe non-EIAEDs.  Patients who must begin EIAED therapy while 
on study will be allowed to remain. 
3.1.26 
Patients must not be taking cytochrome P450 enzyme-inducing 
antiepileptic drugs (phenytoin, carbamazepine or phenobarbital), St 
John's Wort, ketoconazole, dexamethasone, the dysrhythmic drugs 
(terfenadine, quinidine, procainamide, sotalol, probucol, bepridil, 
indapamide or flecainide), haloperidol, risperidone, rifampin, 
grapefruit, or grapefruit juice within two weeks of randomization and 
during the course of therapy (Appendix VI has a list of additional 
medications which have the potential for interaction.) 
3.1.27 
Patients may have received targeted agents (angiogenesis inhibitors, 
EGFR inhibitors, mTOR inhibitors, PI3K inhibitors, etc.), however 
patients must have discontinued treatment with the targeted agent(s) 
at least 4 weeks prior to enrollment. If the patient stopped targeted 
agent(s) due to unresolved or persistent grade 3 or 4 toxicity, patient 
cannot be enrolled onto the study regardless of the length of time 
since discontinuation of treatment with targeted agent(s). 
 
 
 
 
 
Physician Signature 
 
Date 
OPTIONAL: This signature line is provided for use by institutions wishing to 
use the eligibility checklist as source documentation. 
 
_____
Rev. 2/13 
_____
_____
_____
_____
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4. 
Randomization Procedures 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
Prior to the recruitment of a patient for this study, investigators must be registered 
members of a Cooperative Group. Each investigator must have an NCI investigator 
number and must maintain an “active” investigator registration status through the annual 
submission of a complete investigator registration packet (FDA Form 1572 with original 
signature, current CV, Supplemental Investigator Data Form with signature, and 
Financial Disclosure Form with original signature) to the Pharmaceutical Management 
Branch, CTEP, DCTD, NCI.  These forms are available on the CTSU Web site (enter 
credentials at https://www.ctsu.org; then click on the Register tab) or by calling the PMB 
at 240-276-6575 Monday through Friday between 8:30 a.m. and 4:30 p.m. Eastern time. 
Each investigator or group of investigators at a clinical site must obtain IRB approval for 
this protocol and submit IRB approval and supporting documentation to the CTSU 
Regulatory Office before they can enroll patients. Study centers can check the status of 
their registration packets by querying the Regulatory Support System (RSS) site 
registration status page of the CTSU member web site by entering credentials at 
https://www.ctsu.org. 
Requirements for E2809 site registration: 
· 
CTSU IRB Certification 
· 
CTSU IRB/Regulatory Approval Transmittal Sheet 
Submitting Regulatory Documents 
Before an ECOG-ACRIN Institution may enter patients, protocol specific 
regulatory documents must be submitted to the CTSU Regulatory Office at the 
following address:   
 
CTSU Regulatory Office 
 
Coalition of National Cancer Cooperative Groups 
 
1818 Market Street, Suite 1100 
 
Philadelphia, PA 19103 
 
FAX: (215) 569-0206 
Required Protocol Specific Regulatory Documents 
1. 
CTSU Regulatory Transmittal Form. 
2. 
Copy of IRB Informed Consent Document. 
NOTE:  
Any deletion or substantive modification of information 
concerning risks or alternative procedures contained in the 
sample informed consent document must be justified in writing 
by the investigator and approved by the IRB. 
3. 
A. CTSU IRB Certification Form. 
 
Or 
B.  
OMB # No. 0990-0263 (replaces form 310) 
 
Or 
 
C.  
IRB Approval Letter 
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NOTE: 
The above submissions must include the following details: 
· 
Indicate all sites approved for the protocol under an assurance 
number. 
· 
OHRP assurance number of reviewing IRB 
· 
Full protocol title and number 
· 
Version Date 
· 
Type of review (full board vs. expedited) 
· 
Date of review. 
· 
Signature of IRB official 
4. 
Investigator’s Statement 
The Investigator’s Statement documents that the Investigator has read this 
protocol, received IRB approval and will obtain informed consent in writing 
for patients who meet the eligibility criteria. 
NOTE: 
This form only needs to be submitted by the Principal 
Investigator, not for each sub-investigator. 
Before submission, confirm the following on the Investigator’s Statement: 
· 
All fields are complete 
· 
The statement is signed by the Principal Investigator 
The CTSU encourages you to link to the following CTSU RSS webpage so that 
more information on RSS2.0 as well as the submission forms can be accessed. 
Log into http://www.ctsu.org and click on the Regulatory tab to access the RSS 
webpage. If you have questions regarding regulatory document submission, please 
telephone the CTSU Help Desk at 1-888-823-5923 or E-mail 
CTSUContact@westat.com. 
Patients must not start protocol treatment prior to randomization. 
Treatment should start within seven working days after randomization. 
Patient registration can occur only after pre-treatment evaluation is complete, eligibility 
criteria have been met, and the study site is listed as ‘approved’ in the CTSU RSS.  
Patients must have signed and dated all applicable consents and authorization forms.   
All site staff (Lead Group and CTSU Sites) will use OPEN to enroll patients to this study.  
OPEN can be accessed at https://open.ctsu.org or from the OPEN tab on the CTSU 
members’ side of the website at https://www.ctsu.org. 
Prior to accessing OPEN site staff should verify the following: 
· 
All eligibility criteria have been met within the protocol stated timeframes. Site staff 
should use the registration forms provided on the group or CTSU web site as a tool 
to verify eligibility. 
· 
All patients have signed an appropriate consent form and HIPAA 
authorization form (if applicable).  
Access requirements for OPEN: 
· 
Site staff will need to be registered with CTEP and have a valid and active CTEP-
IAM account. This is the same account (user id and password) used for the CTSU 
members' web site.  
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· 
To perform registrations, the site user must have been assigned the 'Registrar' role 
on the relevant Group or CTSU roster.  
· 
To perform registrations on protocols for which you are a member of the Lead Group, 
you must have an equivalent 'Registrar' role on the Lead Group roster. Role 
assignments are handled through the Groups in which you are a member  
· 
To perform registrations to trials accessed via the CTSU mechanism (i.e., non-Lead 
Group registrations) you must have the role of Registrar on the CTSU roster. Site 
and/or Data Administrators can manage CTSU roster roles via the new Site Roles 
maintenance feature under RSS on the CTSU members' web site. This will allow 
them to assign staff the "Registrar" role.  
NOTE: 
The OPEN system will provide the site with a printable confirmation of 
registration and treatment information. Please print this confirmation for your 
records.  
Further instructional information is provided on the OPEN tab of the CTSU members’ 
side of the CTSU website at https://www.ctsu.org or at https://open.ctsu.org. For any 
additional questions contact the CTSU Help Desk at 1-888-823-5923 or 
ctsucontact@westat.com. 
4.1 
Protocol Number  
4.2 
Investigator Identification  
4.2.1 
Institution and affiliate name (Institution CTEP ID) 
4.2.2 
Investigator’s name (NCI number) 
4.2.3 
Cooperative Group Credit 
4.2.4 
Credit Investigator 
4.2.5 
Protocol specific contact information 
4.3 
Patient Identification  
4.3.1 
Patient’s initials (first and last) 
4.3.2 
Patient’s Hospital ID and/or Social Security number 
4.3.3 
Patient demographics 
4.3.3.1 
Gender 
4.3.3.2 
Birth date 
4.3.3.3 
Race 
4.3.3.4 
Ethnicity 
4.3.3.5 
Nine-digit ZIP code 
4.3.3.6 
Method of payment 
4.3.3.7 
Country of residence 
4.4 
Eligibility Verification  
Patients must meet all of the eligibility requirements listed in Section 3.1.  An 
eligibility checklist has been appended to the protocol.  A confirmation of 

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randomization will be forwarded by the ECOG-ACRIN Operations Office – 
Boston. 
4.5 
Stratification Factors 
4.5.1 
Gleason Score 
· 
≤ 6 
· 
7 
· 
8 to 10 
4.5.2 
Prior Hormonal Therapy 
· 
Yes 
· 
No 
4.6 
Additional Requirements  
4.6.1 
Patients must provide a signed and dated, written informed consent 
form. 
4.6.2 
Specimens are to be submitted for laboratory research studies as 
outlined in Section 10. 
NOTE: 
All specimens submitted are to be entered and tracked via 
the online ECOG-ACRIN Sample Tracking System (STS). 
Any case reimbursements associated with specimen 
submissions may not be captured if specimens are not 
logged into STS. See Section 10. 
4.7 
Investigator Drug Brochure and Safety Alerts 
MK-2206 is an INVESTIGATIONAL AGENT (NSC 749607; IND 109493). A copy 
of the Investigator’s Drug Brochure (IDB) can be requested from the PMB (See 
Section 8.1.1). The IDB provides relevant and current scientific information about 
the investigational product. The IDB should be submitted to your IRB/EC 
according to GCP regulations. The IDB and any correspondence to the 
Institutional Review Board (IRB)/Ethics Committee (EC) should be kept in the 
E2809 regulatory files. 
Should any SAE report on this study qualify as a safety alert report requiring 
expedited reporting, the SAE report will be sent by the sponsors to regulatory 
authorities globally (including the FDA) and ECOG-ACRIN. ECOG-ACRIN, 
following regulatory review, will disseminate these safety alert reports to all 
ECOG-ACRIN investigators in the bimonthly group mailings. These reports 
should be forwarded to your IRB/EC within 90 days of receipt for review. 
Reporting instructions are provided with each safety alert. These safety alerts 
and any correspondence to your IRB/EC should be maintained in your E2809 
study files. 
4.8 
Instructions for Patients who Do Not Start Assigned Protocol Treatment  
If a patient does not receive any assigned protocol treatment, baseline and 
follow-up data will still be collected and must be submitted according to the 
instructions in the E2809 Forms Packet. Document the reason for not starting 
protocol treatment on the off-treatment form. Also report the date and type of the 
first non-protocol treatment that the patient receives. 
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5. 
Treatment Plan 
5.1 
Administration Schedule 
1 Cycle = 28 days = 4 weeks. Treatment will be administered on an outpatient 
basis. 
NOTE: 
Reported adverse events and potential risks for both MK-2206 and 
Bicalutamide are described in Sections 5.3, and 8.2.10. Appropriate 
dose modifications for MK-2206 are described in Section 5.4. No 
investigational or commercial agents or therapies, other than those 
described below, may be administered with the intent to treat the 
patient’s malignancy while on study.  There are no dose modifications 
for bicalutamide.  
NOTE: 
Patients will be asked to complete a Patient Medication Calendar 
(Appendix IV) at home to keep a record of pills taken each day as well 
as omissions, side-effects, other medications, etc. Pill counts will also 
be made by a study monitor at each follow-up. 
5.1.1 
Treatment ARM A 
Cycles 1-3 (Weeks 1-12): observation without treatment 
NOTE: 
Patients with a PSA rise of ≥ 50 % above baseline may 
start bicalutamide early (See Section 5.6.1.1). 
Cycles 4-11 (Weeks 13-44): bicalutamide (Casodex) 50 mg/daily, 
orally, continuously to the end of study. 
NOTE: 
If by the end of Cycle 11 (week 44) patient achieved a PSA 
decline of ≥ 50% in the absence of toxicity or progression, 
patient may continue on bicalutamide to the completion of 
Cycle 18 (week 72). If criteria was not met, patient must 
come off-treatment after completion of Cycle 11 (week 44). 
(See Sections 5.6.1.2 and 5.6.1.3). 
5.1.2 
Treatment ARM B 
NOTE: 
To prevent phototoxicity patients should avoid exposure to 
the sun and wear protective clothing while on MK-2206. 
Cycles 1-3 (Weeks 1-12): MK-2206 200 mg once per week, orally. 
Should be taken at approximately the same time each week 2 hours 
before or two hours after a meal. 
ECG monitoring prior to and during MK2206 administration 
On day 1 of cycle 1, the patient will take the medication in the clinic.  
· 
Prior to drug administration obtain ONE ECG 
· 
If QTc is ≤ 480 msec administer MK2206. Repeat ONE ECG 
within 4 to 10 hours after the treatment. 
· 
If QTc remains ≤ 480 msec  one ECG will be performed once, at 
random, on day 1 of any subsequent treatment cycle. 
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If the pre-treatment or post-treatment QTc value is greater than 480 
and less than 515 msec  
a. Measure serum phosphorous, potassium, magnesium, troponin, 
and calcium, and the patient must receive supplements to correct 
any low values.  
b. After correction of imbalances obtain three ECG’s at least 5 
minutes apart, so as to obtain an average pre-treatment QTc 
reading. 
c. Notify CTEP. Any final decisions concerning any dose 
modification/interruptions or patient discontinuing study drug 
permanently should be based on QTc calculations.  
d. If treatment is given, the drug must be taken in the office followed 
by three ECG’s at least 5 minutes apart within 4 to 10 hours after 
MK2206 administration to obtain a post-treatment average.  
e. A weekly ECG prior to dosing must be obtained at either the clinic 
or the local cardiologist to measure QTc.  
f. If QTc remains abnormal refer to a specialist if clinically indicated. 
g. At the end of the cycle QTc status should be re-evaluated.  
· 
if the QTc is less or equal than 480 msec monitor ECG only 
randomly.   
· 
if the QTc value is greater than 480 and less than 515 msec 
further discussion regarding continuation of the patient  on the 
same dose and in the study should be initiated between the 
investigator and CTEP. 
In general, there will be dose reductions for:  
· 
Multiple QTc equal or greater than 480  and less than 515 msec 
· 
Repeat dosing delays due to prolonged QTc intervals 
If QTc ≥ 515 msec  MK2206 will be discontinued 
All cardiac events should be treated as per the local standard of care 
and referred to a specialist by the investigator if clinically indicated. 
NOTE: 
Patients with a PSA rise of ≥ 50 % above baseline may 
start bicalutamide early (See Section 5.6.2.1). 
Cycles 4-11 (Weeks 13-44): Continue MK-2206 200 mg once per 
week, orally. Start bicalutamide (Casodex) 50 mg/daily, orally, on a 
continuous basis. 
NOTE: 
Patients on MK2206 alone that reach a PSA < 0.2 ng/mL 
by week 12 will NOT receive bicalutamide until the PSA 
rises to ≥ 0.2 ng/mL and is confirmed on a second 
determination 2 weeks later. Only after confirmation is 
obtained will bicalutamide be added to the patient’s 
treatment regimen to be continued through the end of 
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NOTE: 
If by the end of Cycle 11, patient achieved a PSA decline 
of ≥ 50% in the absence of toxicity or progression, patient 
may continue on the combination of bicalutamide and MK-
2206 to the completion of Cycle 18. If criteria was not met, 
patient must come off-treatment after completion of Cycle 
11. (See Section 5.6.2.3). 
5.2 
Adverse Event Reporting Requirements 
5.2.1 
Purpose 
Adverse event data collection and reporting, which are required as 
part of every clinical trial, are done to ensure the safety of patients 
enrolled in the studies as well as those who will enroll in future studies 
using similar agents. Adverse events are reported in a routine manner 
at scheduled times during a trial (please refer to the E2809 Forms 
Packet for the list of forms with directions for routine adverse event 
reporting).  Additionally, certain adverse events must be reported in 
an expedited manner for more timely monitoring of patient safety and 
care. The following sections provide information about expedited 
reporting. 
5.2.2 
Determination of Reporting Requirements 
Reporting requirements may include the following considerations: 1) 
whether the patient has received an investigational or commercial 
agent; 2) the characteristics of the adverse event including the grade 
(severity), the relationship to the study therapy (attribution), and the 
prior experience (expectedness) of the adverse event; 3) the phase 
(1, 2, or 3) of the trial; and 4) whether or not hospitalization or 
prolongation of hospitalization was associated with the event. 
An investigational agent is a protocol drug administered under an 
Investigational New Drug Application (IND). In some instances, the 
investigational agent may be available commercially, but is actually 
being tested for indications not included in the approved package 
label. 
Commercial agents are those agents not provided under an IND but 
obtained instead from a commercial source. The NCI, rather than a 
commercial distributor, may on some occasions distribute commercial 
agents for a trial. 
When a study arm includes both investigational and commercial 
agents, the following rules apply. 
· 
Concurrent administration: When an investigational agent(s) is 
used in combination with a commercial agent(s), the combination 
is considered to be investigational and expedited reporting of 
adverse events would follow the guidelines for investigational 
agents. 
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Steps to determine if an adverse event is to be reported in an 
expedited manner: 
Step 1: Identify the type of event: The descriptions and grading 
scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0 will be 
utilized for AE reporting.  All appropriate treatment areas 
should have access to a copy of the CTCAE version 4.0.  A 
copy of the CTCAE version 4.0 can be downloaded from the 
CTEP website at http://ctep.cancer.gov.   
Step 2: Grade the event using the NCI CTCAE version 4.0. 
Step 3: Determine whether the adverse event is related to the 
protocol therapy (investigational or commercial). Attribution 
categories are as follows: Unrelated, Unlikely, Possible, 
Probable, and Definite. 
Step 4: Determine the prior experience of the adverse event. 
Expected events are those that have been previously 
identified as resulting from administration of the agent. An 
adverse event is considered unexpected, for expedited 
reporting purposes only, when either the type of event or the 
severity of the event is NOT listed in:  
· 
Arm A – the drug package insert or protocol  
· 
Arm B – the current NCI Specific Protocol Exceptions to 
Expedited Reporting (SPEER) for MK-2206  
NOTE: 
The NCI SPEER for MK-2206 is included in 
Section 5.3 of the protocol.  
· 
FOR THIS PROTOCOL, events listed in the SPEER for 
MK-2206 should be considered EXPECTED if the grade 
being reported is the same or lower than the grade noted 
in the parentheses next to the AE in the SPEER.  Events 
listed in the SPEER column should be considered 
UNEXPECTED if the grade being reported exceeds the 
grade noted in parentheses next to the AE in the 
SPEER. 
· 
The SPEER is presented in the last column of the 
CAEPR and identified with bold and italicized text. 
Step 5: Review the ”Additional instructions, requirements, and 
exceptions for protocol E2809” table in section 5.2.6 and 
footnote b in Section 5.2.7 for protocol and/or ECOG-ACRIN 
specific requirements for expedited reporting of specific 
adverse events that require special monitoring.   
NOTE: 
For general questions regarding expedited 
reporting requirements, please contact the AEMD 
Help Desk at aemd@tech-res.com or 301-897-
7497. 
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5.2.3 
Reporting Procedure 
This study requires that expedited adverse event reporting use 
CTEP’s Adverse Event Reporting System (CTEP-AERS). CTEP’s 
guidelines for CTEP-AERS can be found at http://ctep.cancer.gov.  A 
CTEP-AERS report must be submitted electronically to ECOG-ACRIN 
and the appropriate regulatory agencies via the CTEP-AERS Web-
based application located at http://ctep.cancer.gov. 
In the rare event when Internet connectivity is disrupted a 24-hour 
notification is to be made by telephone to 
· 
the AE Team at ECOG-ACRIN (617-632-3610)for Arm A and B 
· 
the FDA (800-332-0178) for Arm A 
· 
the NCI (301-897-7497) for Arm B 
An electronic report MUST be submitted immediately upon re-
establishment of internet connection. 
Supporting and follow up data:  Any supporting or follow up 
documentation must be faxed to ECOG-ACRIN (617-632-2990), 
Attention: AE within 48-72 hours. In addition, supporting or follow up 
documentation must be faxed to the FDA (800-332-0178) for Arm A 
and the NCI (301-230-0159) for Arm B in the same timeframe. 
NCI Technical Help Desk: For any technical questions or system 
problems regarding the use of the CTEP-AERS application, please 
contact the NCI Technical Help Desk at ncictephelp@ctep.nci.nih.gov 
or by phone at 1-888-283-7457. 
5.2.4 
When to Report an Event in an Expedited Manner 
Some adverse events require 24-hour notification (refer to Section 
5.2.6). Please complete a 24-Hour Notification Report via the NCl 
CTEP-AERS website (http://ctep.cancer.gov) within 24 hours of 
learning of the event.  The full CTEP-AERS report must be completed 
and submitted via CTEP-AERS within 5 calendar days. 
If the CTEP-AERS system is down, a 24-hour notification call must be 
made to ECOG-ACRIN (617-632-3610) and to NCI (301-897-7497). 
Once the system is restored, a 24-hour Notification Report must be 
entered into the CTEP-AERS system by the original submitter of the 
report at the site. 
When an adverse event requires expedited reporting, submit a full 
CTEP-AERS report within the timeframes outlined in Sections 5.2.6 
and 5.2.7. 
NOTE: 
Adverse events that meet the reporting requirements in 
Sections 5.2.6 or 5.2.7 and occur within 30 days of the last 
dose of protocol treatment must be reported on an 
expedited adverse event report form (using CTEP-AERS). 
For any adverse events that occur more than 30 days after 
the last dose of treatment, only those that have an 
attribution of possibly, probably, or definitely AND meet the 
reporting requirements in Sections 5.2.6 or 5.2.7 must be 
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reported on an expedited adverse event report form (using 
CTEP-AERS). 
5.2.5 
Other Recipients of Adverse Event Reports 
DCTD/NCI will notify ECOG-ACRIN/pharmaceutical collaborator(s) of 
all AEs reported to FDA. Any additional written AE information 
requested by ECOG-ACRIN MUST be submitted to BOTH the NCI 
and ECOG-ACRIN. 
Adverse events determined to be reportable must also be reported by 
the institution, according to the local policy and procedures, to the 
Institutional Review Board responsible for oversight of the patient. 

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5.2.6 
Expedited Reporting for Investigational Agents 
Phase 2 and 3 Trials Utilizing an Agent under a CTEP IND:  CTEP-AERS Expedited Reporting 
Requirements for Adverse Events That Occur Within 30 Days1 of the Last Dose of Investigational 
Agent [MK-2206] in this Study (Arm B) OR Within 30 Days of the Last Dose of Any Protocol 
Treatment. 
 
 
Attribution 
 
Grade 1 
 
Grade 2 
 
Grade 2 
 
Grade 3 
 
Grade 3 
Grades 
4 & 52 
Grades 
4 & 52 
Unexpected 
and 
Expected 
 
 
Unexpected 
 
 
Expected 
Unexpected 
Expected 
Unexpected 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  
 
CTEP-AERS 10 calendar day report: 
· 
Grade 3 unexpected events with hospitalization or prolongation of hospitalization 
· 
Grade 5 expected events 
2 Although a 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. 
   Please see additional information below under section entitled “Additional instructions, requirements, and exceptions for 
protocol E2809” 
March 2005 
NOTE: 
All deaths on study require both routine and expedited reporting regardless of causality.  
Attribution to treatment or other cause should be provided. 
· 
Expedited AE reporting timelines: 
➢ 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. 

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➢ 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 with the exception of any events identified as protocol-specific expedited 
adverse event reporting exclusions. 
· 
Any event that results in persistent or significant disability/incapacity, congenital anomaly, or 
birth defect 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 provided during trial registration on all 
reports. 
· 
Hospitalizations are defined as lasting 24 hours or longer and these events must be reported via CTEP-
AERS. 

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Additional instructions, requirements and exceptions for protocol E2809 
1.  Additional Instructions: 
➢ With respect to determining the specific day by which the event must be reported, the 
day the reporter learns of the adverse event constitutes “Day 0” 
➢ For grade 2 and 3 unexpected events, CTEP-AERS reporting is only required if the 
event is related to the investigational agent(s); it is not required if the event is related 
only to the commercial agent(s) included in the protocol treatment.   
NOTE: For grade 3 unexpected events with hospitalization lasting  24 hours (or 
prolonged hospitalization), an CTEP-AERS report is required even if the event is 
unrelated to the investigational agent(s). 
➢ For instructions on how to specifically report events that result in persistent or 
significant disability/incapacity, congenital anomaly, or birth defect events via CTEP-
AERS, please contact the AEMD Help Desk at aemd@tech-res.com  or 301-897-
7497. This will need to be discussed on a case-by-case basis. 
2.  ECOG-ACRIN and Protocol Specific expedited reporting requirements: 
The adverse events listed below also require expedited reporting for this trial: 
ECOG-ACRIN specific expedited reporting requirements: 
➢ 
Hospitalizations:  Any grade 1 or 2 adverse event with precipitates a 
hospitalization lasting > 24 hours (or prolongs hospitalization) must be reported 
via CTEP-AERS within 10 calendar days of learning of the event regardless of the 
attribution and designation as expected or unexpected. 

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5.2.7 
Expedited Reporting for Commercial Agents 
Commercial reporting requirements are provided below. The 
commercial agent used in arm A of this study Bicalutamide. 
Expedited reporting requirements for adverse events experienced by patients on arm(s) with commercial agents 
only – Arm A 
Attribution 
Grade 4 
Grade 5a 
ECOG-ACRIN and 
Protocol-Specific 
Requirements 
Unexpected 
Expected 
Unexpected 
Expected 
See footnote  
(b) for special 
requirements. 
Unrelated 
or Unlikely 
 
 
7 calendar 
days 
7 calendar 
days 
Possible,  
Probable,  
Definite 
7 calendar 
days 
 
7 calendar 
days 
7 calendar 
days 
7 Calendar Days: Indicates a full CTEP-AERS report is to be submitted within 7 calendar days of learning of the 
event. 
a 
This includes all deaths within 30 days of the last dose of treatment regardless of attribution.  
NOTE: Any death that occurs > 30 days after the last dose of treatment and is attributed possibly, 
probably, or definitely to the treatment must be reported within 7 calendar days of learning of 
the event.   
b 
Protocol-specific expedited reporting requirements: The adverse events listed below also require expedited 
reporting for this trial: 
Serious Events: 
Any event following treatment that results in persistent or significant 
disabilities/incapacities, congenital anomalies, or birth defects must be reported via CTEP-
AERS within 7 calendar days of learning of the event.  For instructions on how to 
specifically report these events via CTEP-AERS, please contact the AEMD Help Desk at 
aemd@tech-res.com or 301-897-7497.  This will need to be discussed on a case-by-case 
basis. 
5.2.8 
Reporting Second Primary Cancers 
All cases of second primary cancers, including acute myeloid 
leukemia (AML) and myelodysplastic syndrome (MDS), that occur 
following treatment on NCI-sponsored trials must be reported to 
ECOG-ACRIN: 
· 
A second malignancy is a cancer that is UNRELATED to any 
prior anti-cancer treatment (including the treatment on this 
protocol).  Second malignancies require ONLY routine reporting 
as follows: 
1. Submit a completed Second Primary Form within 30 days to 
ECOG-ACRIN at 
ECOG-ACRIN Operations Office – Boston 
FSTRF 
900 Commonwealth Avenue 
Boston, MA 02215 
2. Submit a copy of the pathology report to ECOG-ACRIN 
confirming the diagnosis. 
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3. If the patient has been diagnosed with AML/MDS, submit a 
copy of the cytogenetics report (if available) to ECOG-ACRIN 
· 
A secondary malignancy is a cancer CAUSED BY any prior anti-
cancer treatment (including the treatment on this protocol). 
Secondary malignancies require both routine and expedited 
reporting as follows: 
1. Submit a completed Second Primary Form within 30 days to 
ECOG-ACRIN at 
ECOG-ACRIN Operations Office – Boston 
FSTRF 
900 Commonwealth Avenue 
Boston, MA 02215 
2. Report the diagnosis via CTEP-AERS at http://ctep.cancer.gov 
Report under a.) leukemia secondary to oncology 
chemotherapy, b.) myelodysplastic syndrome, or c.) 
treatment related secondary malignancy 
3. Submit a copy of the pathology report to ECOG-ACRIN and 
NCI/CTEP confirming the diagnosis. 
4. If the patient has been diagnosed with AML/MDS, submit a 
copy of the cytogenetics report (if available) to ECOG-ACRIN 
and NCI/CTEP. 
NOTE: 
The Second Primary Form and the CTEP-AERS report 
should not be used to report recurrence or development of 
metastatic disease. 
NOTE: 
If a patient has been enrolled in more than one NCI-
sponsored study, the Second Primary Form must be 
submitted for the most recent trial. ECOG-ACRIN must be 
provided with a copy of the form and the associated 
pathology report and cytogenetics report (if available) even 
if ECOG-ACRIN was not the patient's most recent trial. 
NOTE: 
Once data regarding survival and remission status are no 
longer required by the protocol, no follow-up data should 
be submitted via CTEP-AERS or by the Second Primary 
Form. 

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5.3 
Comprehensive Adverse Events and Potential Risks list (CAEPR) for MK-2206 
(NSC 749607) 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a 
single list of reported and/or potential adverse events (AE) associated with an 
agent using a uniform presentation of events by body system. In addition to the 
comprehensive list, a subset, the Specific Protocol Exceptions to Expedited 
Reporting (SPEER), appears in a separate column and is identified with bold and 
italicized text. This subset of AEs (SPEER) is a list of events that are protocol 
specific exceptions to expedited reporting to NCI via CTEP-AERS (except as 
noted below). Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting 
Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguide
lines.pdf for further clarification. Frequency is provided based on 193 patients. 
Below is the CAEPR for MK-2206. 
NOTE: 
FOR THIS PROTOCOL, events listed in the SPEER column should 
be considered EXPECTED if the grade being reported is the same or 
lower than the grade noted in the parentheses next to the AE in the 
SPEER.  Events listed in the SPEER column should be considered 
UNEXPECTED if the grade being reported exceeds the grade noted 
in parentheses next to the AE in the SPEER. 
Version 2.1, March 22, 20131 
 
 Adverse Events with Possible  
 Relationship to MK-2206 
 (CTCAE 4.0 Term) 
[n= 193] 
 
 
 
 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 
  
 
Constipation 
 
  
Diarrhea 
 
 
 Diarrhea (Gr 2) 
 
Mucositis oral 
 
 Mucositis oral (Gr 2) 
Nausea 
 
 
 Nausea (Gr 2) 
 
Vomiting 
 
 Vomiting (Gr 2) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Fatigue 
 
 Fatigue (Gr 2) 
 
Fever 
 
 Fever (Gr 2) 
IMMUNE SYSTEM DISORDERS 
  
 
Allergic reaction 
 
  
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INVESTIGATIONS 
  
 
Alanine aminotransferase 
increased 
 
  
 
Alkaline phosphatase 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 
 
  
 
Neutrophil count decreased 
 
  
 
Platelet count decreased 
 
  
 
White blood cell decreased 
 
 White blood cell decreased 
(Gr 2) 
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
 Anorexia (Gr 2) 
 
Hyperglycemia 
 
 Hyperglycemia (Gr 2) 
 
Hypokalemia 
 
  
 
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) 
1 This table will be updated as the toxicity profile of the agent is revised. Updates will be distributed to all 
Principal Investigators at the time of revision. The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV. Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail. 
Also reported on MK-2206 trials but with the relationship to MK-2206 still undetermined: 
CARDIAC DISORDERS - Atrioventricular block complete; Palpitations 
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; 
Dry mouth; Dyspepsia; Dysphagia; Gastritis; Lip pain; Oral 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 

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INFECTIONS AND INFESTATIONS - Infections and infestations - Other (herpetic vesicular 
rash [due to herpes zoster infection]); Infections and infestations - Other (oral herpes); Nail 
infection; Paronychia; Rhinitis infective; Sepsis; Skin infection; Urinary tract infection 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Fall 
INVESTIGATIONS - Activated partial thromboplastin time prolonged; Aspartate 
aminotransferase increased; Blood bilirubin increased; INR increased; Investigations - Other 
(blood LDH increased); Investigations - Other (hyperinsulinemia); Investigations - Other 
(glucose urine present); Lipase increased; Serum amylase increased; Weight gain; Weight loss 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hypercalcemia; Hyperkalemia; 
Hypermagnesemia; Hypoalbuminemia; Hypocalcemia; 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; Lethargy; Presyncope; Reversible 
posterior leukoencephalopathy syndrome; Seizure 
PSYCHIATRIC DISORDERS - Anxiety; Confusion; Depression; Insomnia 
RENAL AND URINARY DISORDERS - Acute kidney injury; Proteinuria; Renal and urinary 
disorders - Other (renal tubular necrosis); Urinary incontinence; Urinary tract pain 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Gynecomastia; Reproductive 
system and breast disorders - Other (genital hemorrhage); Vaginal hemorrhage 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Bronchial obstruction; 
Cough; Dyspnea; Hypoxia; Pneumonitis; Pulmonary edema; Respiratory, thoracic and 
mediastinal disorders - Other (oropharyngeal pain); Sore throat 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Erythema multiforme; 
Hyperhidrosis; Palmar-plantar erythrodysesthesia syndrome; Photosensitivity; Purpura; Rash 
acneiform; Skin and subcutaneous tissue disorders - Other (skin discoloration); Skin and 
subcutaneous tissue disorders - Other (skin irritation); 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. 

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5.4 
Dose Modifications  
All toxicities should be graded according to the CTEP Version 4.0 of the NCI 
Common Terminology Criteria for Adverse Events (CTCAE). 
The CTEP Version 4.0 of 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 the CTEP 
Active Version of CTCAE. 
Dose reductions will be performed as outlined below depending on the type and 
severity of the toxicity encountered, provided that the criteria have not been met 
for subject withdrawal from study. 
Patients will be withdrawn from the study if they fail to recover to CTCAE grade 0 
to 2 (or within 1 grade of starting values of pre-existing laboratory abnormalities) 
from a treatment-related toxicity within 42 days (leading to treatment delay of > 
42 days). 
Dose modifications are not necessary for Grade 1 or 2 toxicities, except changes 
in ECG (follow section 5.4.3 ECG monitoring) and grade 2 or greater drug 
included papulo-macular rash (follow section 5.4.5 instructions). 
No dose level modifications of bicalutamide are allowed. 
5.4.1 
Dose Levels 
Arm A: 
Dose Level 
Bicalutamide 
0 
(Cycle 4 +)*  
50 mg/daily 
-1 
No dose modifications 
-2 
No dose modifications 
* Patients with a PSA rise of > 50% above baseline may start bicalutamide 
early. 
5.4.2 
Arm B: 
Dose Level 
Bicalutamide 
MK-2206 
0 
(Cycle 4 +)* 
50 mg/daily 
(All cycles) 
200 mg once per week 
-1 
No dose modifications 
135 mg once per week 
-2 
No dose modifications 
90 mg once per week 
* Patients with a PSA rise of > 50% above baseline may start bicalutamide 
early. 
NOTE:  
Patients requiring a dose reduction below the -2 dose level 
must be taken off study. 
Rev. 2/13 
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5.4.3 
Suggested Dose Modifications 
There will be no dose reductions for bicalutamide. In case of CTCAE 
Grade 3 or 4 transaminase elevations both bicalutamide and MK-
2206 will be stopped until the event resolves to ≤ Grade 1. 
In all cases of toxicity that cannot be attributed to MK-2206 alone, 
both drugs will be stopped until the event resolves to ≤ Grade 1. 
Treatment will be restarted with full dose of bicalutamide and MK-
2206 should be reduced according to the guidelines provided.  
For toxicities that are attributed to MK-2206 alone, follow the chart 
below regarding MK-2206 dose modification, but bicalutamide will 
continue at its normal dosage. 
 
For Grade 3-4 toxicities at least possibly related to study medication 
Toxicities 
Occurrence 
Suggested MK-2206 Dose Modifications 
Bone marrow suppression 
ANC <0.5 ng/μL for > 7 days 
ANC <1.0 ng/μL with fever 
(temperature of ≥100.5o F 
/38.5oC) 
Platelet count <25 ng/μL 
Liver Toxicity 
CTCAE Grade 3/4 
transaminase elevations 
Other CTCAE Grade 3 or 4 
non-hematologic toxicities 
1st occurrence 
 
 
 
 
 
 
1. Interrupt MK-2206 until recovery to ≤ Grade 1 
2. Treatment according to the findings 
3. Restart with reduced dose 
4. Increase to 200 mg once per week if toxicity is 
maintained at ≤ Grade 1 within 28 days 
5. Discontinue from study therapy if the event has 
not resolved to ≤ Grade 1 within 42 days or 
event occurs during therapy at the 135 mg once 
per week reduced dose. 
2nd occurrence 
 
1. Interrupt MK-2206 until recovery to ≤ Grade 1 
2. Treatment according to the findings 
3. Restart with reduced dose 
4. Increase to 200 mg once per week if toxicity is 
maintained at ≤ Grade 1 within 28 days 
5. Discontinue from study therapy if the event has 
not resolved to ≤ Grade 1 within 42 days or 
event occurs during therapy at the 90 mg once 
per week reduced dose. 
3rd occurrence 
Discontinue from study treatment. 
Abbreviations: ANC (absolute neutrophil count)  
ECG monitoring prior to and during MK2206 administration 
On day 1 of cycle 1, the patient will take the medication in the clinic.  
· 
Prior to drug administration obtain ONE ECG. 
· 
If QTc is ≤ 480 msec administer MK2206. Repeat ONE ECG 
within 4 to 10 hours after the treatment. 
· 
If QTc remains ≤ 480 msec one ECG will be performed once, at 
random, on day 1 of any subsequent treatment cycle. 
Rev. 4/12,  
        9/12 
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NCI Update Date: July 2, 2013 
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If the pre-treatment or post-treatment QTc value is greater than 480 
and less than 515 msec  
a. Measure serum phosphorous, potassium, magnesium, troponin, 
and calcium, and the patient must receive supplements to correct 
any low values.  
b. After correction of imbalances obtain three ECG’s at least 5 
minutes apart, so as to obtain an average pre-treatment QTc 
reading.  
c. Notify CTEP. Any final decisions concerning any dose 
modification/interruptions or patient discontinuing study drug 
permanently should be based on QTc calculations.  
d. If treatment is given, the drug must be taken in the office followed 
by three ECG’s at least 5 minutes apart within 4 to 10 hours after 
MK2206 administration to obtain a post-treatment average.  
e. A weekly ECG prior to dosing must be obtained at either the clinic 
or the local cardiologist to measure QTc.  
f. If QTc remains abnormal refer to a specialist if clinically indicated. 
g. At the end of the cycle QTc status should be re-evaluated.  
· 
if the QTc is less or equal than 480 msec monitor ECG only 
randomly.   
· 
if the QTc value is greater than 480 and less than 515 msec 
further discussion regarding continuation of the patient  on the 
same dose and in the study should be initiated between the 
investigator and CTEP. 
In general, there will be dose reductions for:  
· 
Multiple QTc equal or greater than 480  and less than 515 msec 
· 
Repeat dosing delays due to prolonged QTc intervals 
If QTc ≥ 515 msec  MK2206 will be discontinued 
All cardiac events should be treated as per the local standard of care 
and referred to a specialist by the investigator if clinically indicated. 
5.4.4 
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 (dose 
modification, etc.). 
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 

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monitoring, for patients requiring treatment of hyperglycemia, should 
be performed with each cycle of MK-2206 therapy. 
5.4.5 
Drug induced maculo-papular rash treatment guide 
In case of grade 2 or greater drug induced papulo-macular rash, use 
the following precautions:  
1. Interrupt MK2206.  
2. Use antihistamines such as Fexofenadine or Loratidine that are not 
CYP3A4 inducers/inhibitors and if needed use anti-pruritic 
medications that are non steroidal such as topical 2% clindamycin and 
non CYP3A4 inducers/inhibitors antibiotics. 
3. If rash does not decrease to grade 1 or less within 2 weeks, 
corticosteroids such as 1% hydrocortisone in a lotion base may be 
used after consultation with Study Chair. 
4. If rash resolves to grade 1 or less within 42 days, restart MK2206 at 
135mg once per week.  If grade 2 or higher rash recurs at the 135 mg 
dose, patient should come off study. If rash persists at grade 1 or less 
during 28 days, the dose may be increased back to 200mg once per 
week or maintained at 135mg once per week at the discretion of the 
principal investigator.  
If the rash recurs again after increasing the dose back to MK2206 
200mg dose follow steps 1- 3 and if the rash decreases to grade 1 or 
less for 28 days re-introduce the MK2206 at 90mg once per week. If 
tolerated at the 90 mg for 28 days may increase MK2206 back to 
200mg once per week or left at 90mg once per week at the discretion 
of the principal investigator. 
5. Patient should be taken off study for a second recurrence of rash at 
a reduced dose level (either 135mg or 90mg) or a third recurrence at 
200mg dose of MK2206. 
5.5 
Supportive Care  
Patients are allowed to receive full supportive care therapies concomitantly 
during the study.  At each visit, appropriate documentation of all forms of 
premedication, supportive care, and concomitant medications must be recorded 
on the CRF.  Concomitant medications and supportive care therapies must also 
be documented at the time of discontinuation and at the 30-day follow-up visit. 
NOTE: 
If the patient has an AE that falls after week 45 they must have a 
return visit for evaluation or communicate by phone within 30 days 
and provide documentation describing the event. 
5.6 
Duration of Therapy  
5.6.1 
Arm A 
5.6.1.1 
Cycles 1-3 (Weeks 1-12) 
· 
Patients with a PSA rise of ≥ 50% above baseline or 
nadir (whichever is lowest) and a rise of at least 5 
ng/mL, confirmed by a repeat PSA at least 2 weeks 
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later, may be started on bicalutamide before the end of 
Cycle 3 (week 12) at the discretion of the treating 
physician. 
· 
Patients with a PSA rise of < 50% above baseline or 
nadir, stable PSA, or declining PSA, will continue 
observation until the end of Cycle 3 (week 12). 
· 
Patients with PSA < 0.2 ng/mL by the end of Cycle 3 
(week 12) will NOT receive bicalutamide until the PSA 
rises to ≥ 0.2 ng/mL and the rise is confirmed on a 
second determination 2 weeks later. 
5.6.1.2 
Cycles 4-11 (Weeks 13-44) 
· 
Patients with a PSA rise of ≥ 50% above baseline or 
nadir (whichever is lowest) and a rise of at least 5 
ng/mL, confirmed by a repeat PSA at least 2 weeks 
later, will be considered failures and removed from 
study. 
· 
Patients with a PSA rise of < 50% above baseline or 
nadir, stable PSA, or declining PSA, will continue on 
bicalutamide to the end of study. 
5.6.1.3 
End of Study 
· 
Patients on Arm A will not be eligible to receive MK-
2206.  
· 
Patients who achieve a reduction in PSA by ≥ 50% 
may continue receiving bicalutamide up to the 
completion of Cycle 18 (week 72) in the absence of 
toxicity, progression or other reason for needing to go 
off study. 
5.6.2 
Arm B 
5.6.2.1 
Cycles 1-3 (Weeks 1-12) 
· 
Patients with a PSA rise of ≥ 50% above baseline or 
nadir (whichever is lowest) and a rise of at least 5 
ng/mL, confirmed by a repeat PSA at least 2 weeks 
later, may be started on bicalutamide before the end of 
Cycle 3 (week 12) at the discretion of the treating 
physician. 
· 
Patients with a PSA rise of < 50% above baseline or 
nadir, stable PSA, or declining PSA, will continue MK-
2206 until the end of Cycle 3 (week 12). 
· 
Patients with PSA < 0.2 ng/mL by the end of Cycle 3 
(Week 12) will NOT receive bicalutamide until the PSA 
rises to ≥ 0.2 ng/mL and the rise is confirmed on a 
second determination 2 weeks later. 

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NCI Update Date: July 2, 2013 
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5.6.2.2 
Cycles 4-11 (Weeks 13-44) 
· 
Patients receiving the combination therapy who 
experience a PSA rise of ≥ 50% above baseline or 
nadir (whichever is lowest) and a rise of at least 5 
ng/mL, confirmed by a repeat PSA at least 2 weeks 
later, will be considered failures and removed from 
study. 
· 
Patients with a PSA rise of < 50% above baseline or 
nadir, stable PSA, or declining PSA, will continue 
therapy to the end of study. 
· 
Patients on MK2206 alone between weeks 13-44 who 
experience a PSA rise to ≥ 0.2 ng/mL, and the rise is 
confirmed on a second determination 2 weeks later, 
will receive bicalutamide to the end of week 44. 
5.6.2.3 
End of Study 
· 
Patients who achieve a reduction in PSA by ≥ 50% 
may continue receiving the combination therapy up to 
the completion of Cycle 18 (week 72), in the absence 
of toxicity, progression, or other reason for needing to 
go off study. 
5.7 
Discontinuation of Therapy 
Patients will receive protocol therapy unless: 
5.7.1 
Progression of Disease 
· 
PSA Progression 
OR 
· 
Clinical progression  
5.7.2 
Unacceptable toxicity – type and grade must be documented on the 
E2809 Adverse Event Form. Patients removed from study for 
unacceptable adverse events will be followed until resolution or 
stabilization of the adverse event. 
5.7.3 
Extraordinary Medical Circumstances: If at any time the constraints of 
this protocol are detrimental to the patient's health, protocol treatment 
should be discontinued. In this event submit forms according to the 
instructions in the E2809 Forms Packet. 
5.7.4 
Patient withdraws consent. 
5.8 
Duration of Follow-up  
For this protocol, all patients, including those who discontinue protocol therapy 
early, will be followed for response until clinical metastatic progression and for 
survival for 10 years from the date of registration.  All patients must also be 
followed through completion of all protocol therapy. 

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6. 
Measurement of Effect 
6.1 
Biochemical Response 
6.1.1 
Complete Response 
Complete biochemical response will be a PSA <0.2 ng/mL (confirmed 
on two consecutive additional determinations taken at least 4 weeks 
apart).  
6.1.2 
Partial Response 
A reduction in PSA ≥ 50% from baseline without evidence of 
progression (confirmed on two consecutive additional determinations 
taken at least 4 weeks apart). 
6.1.3 
Stable Disease  
Patients who do not meet the criteria for response (CR or PR) or 
serological progression for at least 3 months (90 days) will be 
categorized as having stable disease. 
6.1.4 
Progressive Disease  
· 
For patient who achieved a ≥ 50% decline in PSA (confirmed on 
two consecutive additional determinations taken at least 4 weeks 
apart), progression is defined as an increase in PSA value by 50% 
above baseline or nadir (whichever is lowest), confirmed by a 
second PSA rise at least two weeks later. The PSA rise must be 
at least 5 ng/mL. Changes in PSA below 5 ng/mL will not be 
considered assessable for progression. 
· 
For patients with an undetectable PSA nadir (< 0.2 ng/mL 
confirmed on two consecutive additional determinations taken at 
least 4 weeks apart), progression is defined as a PSA rise to the 
detectable range (detectable PSA is ≥ 0.2 ng/mL) confirmed by a 
second PSA rise at least 2 weeks later. 
· 
For patients whose PSA has not decreased by 50%, progression 
is defined as an increase in PSA value ≥ 50% of baseline (on trial) 
or nadir PSA, whichever is lowest, confirmed by a repeat PSA at 
least 2 weeks later. The PSA must have risen by at least 5 ng/mL. 
6.2 
Clinical Progression  
The appearance of new lesions on examination or radiographs (CXR, CT scan, 
MRI scan, or bone scan), or development of symptoms consistent with metastatic 
disease (i.e. bone pain) with or without a concurrent increase in serum PSA from 
baseline. 
6.3 
Survival  
Survival will be measured from the date of randomization. 
6.4 
Time to PSA Progression  
Time to PSA progression is defined as time from registration to first confirmed 
rise in PSA (or development of clinical progression) meeting progressive criteria 
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NCI Update Date: July 2, 2013 
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after starting bicalutamide treatment. The 50% rise of PSA from baseline during 
the first 12 weeks which triggers the early treatment with bicalutamide is not 
considered a PSA progression. 
6.5 
Time to PSA Nadir 
Time to PSA nadir is defined as the time from registration to the date that PSA 
nadir is documented. PSA nadir is defined as the lowest PSA value achieved 
after registration or baseline PSA, whichever is lowest. 
6.6 
PSA Slope  
The change in PSA will be graphically depicted and a PSA slope calculated. The 
change in PSA slope (and PSADT) pre-study, during-study, and off-study will be 
determined to see if the treatments have any disease modifying effects, 
especially in those patients experiencing stable disease. This end-point is 
exploratory, but may help to interpret PSA response. 
6.7 
Symptomatic Deterioration  
Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should 
be classified as having symptomatic deterioration. 
6.8 
Duration of Response 
The period measured from the time that PSA criteria are met for complete or 
partial response (whichever status is recorded first) until the first date that 
progressive disease is documented. 

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7. 
Study Parameters 
7.1 
Therapeutic Parameters  
1. Prestudy scans and x-rays must be done within 8 weeks prior to randomization. 
2. Prestudy CBC (with differential and platelet count) should be done within 4 weeks prior to randomization. 
3. All required prestudy chemistries, as outlined in Section 3.1.13, should be done within 4 weeks prior to 
randomization. 
 
Pre- 
Study 
Cycle 1 
Day 1 
Day 1 of 
Each Cycle 
(Cycles 2-6) 
Day 1 of 
Cycle 7 
(Week 25) 
Day 1 of 
each cycle 
(cycles 8-11) 
Day after 
Cycle 11 
finished  
(Day 1 of 
Week 45) 
Day 1 of 
Each Cycle 
(Cycles 13-
18)6  
End of 
Treatment6 
Follow
-up7 
Medical history, height 
X 
 
 
 
 
 
 
 
 
Concurrent meds 
X 
X 
X 
X 
X 
X 
X 
X 
 
Physical exam, vitals1, weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG performance status 
X 
X 
X 
X 
X 
X 
X 
X 
 
CBC w/diff, plts2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum chemistries3 
X 
X 
X 
X 
X 
X 
X 
X 
 
Total testosterone 
X 
 
 
 
 
X 
 
X 
 
PSA 
X 
X 
X 
X 
X 
X 
X 
X 
X5 
Radiologic evaluation 
X4 
 
 
X4 
 
X4 
X10 
X 
 
ECG 
X 
X11 
(Arm B) 
As indicated 
 
AE Evaluation 
 
X 
X 
X 
X 
X 
X 
X 
X8 
Tumor tissue 
X9 
 
 
 
 
 
 
 
 
1. Blood pressure, pulse  
2. CBCs (with differential and platelet count) which includes WBC, ANC, Platelets, Hgb, and Hct required for protocol therapy must be obtained 
within 4 days of day 1 of treatment cycle.  
3. Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, phosphorus, potassium, total 
protein, SGOT[AST], SGPT[ALT], sodium. There is a +/- 7 day leeway for scheduled tests while on study (leeway does not apply to tests/labs 
required at baseline to determine patient eligibility). For patients with known diabetes: 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 performed with each cycle of MK-2206 therapy. 
4. CXR, CT abdomen/pelvis (or MRI), and bone scan required at baseline, day 1 cycle 7 and end of cycle 11. There is a +/- 7 day leeway for 
Rev. 4/12 
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scheduled tests while on study (leeway does not apply to test/labs required at baseline to determine patient eligibility). 
5. After going off treatment, patients will be evaluated for PSA levels monthly for the first 6 months and then every 3 months until PSA 
progression. 
6. For those patients who continue study treatment after Cycle 11. 
7. Follow-up for study purposes will be every 3 months until 2 years, every 6 months 2-5 years and every year up to 10 years.  
8. Until documentation of progression (serological or clinical). 
9. Submit for patients who consent to allow tissue to be submitted for use in research. See Section 10. 
10. If the patient remains on study after the end of study (Cycle 11), repeat at the end of cycle 18 or sooner if clinically indicated. There is a +/- 7 
day leeway for scheduled tests while on study (leeway does not apply to tests/labs required at baseline to determine patient eligibility). 
11. ECG Monitoring prior to and during MK2206 administration 
On day 1 of cycle 1, the patient will take the medication in the clinic.  
· Prior to drug administration obtain ONE ECG 
· If QTc is ≤ 480 msec administer MK2206. Repeat ONE ECG within 4 to 10 hours after the treatment. 
· If QTc remains ≤ 480 msec one ECG will be performed once, at random, on day 1 of any subsequent treatment cycle. 
If the pre-treatment or post-treatment QTc value is greater than 480 and less than 515 msec  
a. Measure serum phosphorous, potassium, magnesium, troponin, and calcium, and the patient must receive supplements to correct any low 
values.  
b. After correction of imbalances obtain three ECG’s at least 5 minutes apart, so as to obtain an average pre-treatment QTc reading.  
c. Notify CTEP. Any final decisions concerning any dose modification/interruptions or patient discontinuing study drug permanently should be 
based on QTc calculations.  
d. If treatment is given, the drug must be taken in the office followed by three ECG’s at least 5 minutes apart within 4 to 10 hours after 
MK2206 administration to obtain a post-treatment average.  
e. A weekly ECG prior to dosing must be obtained at either the clinic or the local cardiologist to measure QTc.  
f. If QTc remains abnormal refer to a specialist if clinically indicated. 
g. At the end of the cycle QTc status should be re-evaluated.  
· if the QTc is less or equal than 480 msec monitor ECG only randomly.   
· if the QTc value is greater than 480 and less than 515 msec further discussion regarding continuation of the patient  on the same dose 
and in the study should be initiated between the investigator and CTEP. 
In general, there will be dose reductions for:  
· Multiple QTc equal or greater than 480  and less than 515 msec 
· Repeat dosing delays due to prolonged QTc intervals 
If QTc ≥ 515 msec  MK2206 will be discontinued 
All cardiac events should be treated as per the local standard of care and referred to a specialist by the investigator if clinically indicated. 
Rev. 4/12,  
       9/12 
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Version Date: July 31, 2014 
 
NCI Update Date: July 2, 2013 
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8. 
Drug Formulation and Procurement 
8.1 
MK-2206 
8.1.1 
Availability 
NCI supplied agents may be requested by the Principal Investigator 
(or their authorized designee) at each participating institution.  
Pharmaceutical Management Branch (PMB) policy requires that agent 
be shipped directly to the institution where the patient is to be treated.  
PMB does not permit the transfer of agents between institutions 
(unless prior approval from PMB is obtained.)  The CTEP assigned 
protocol number must be used for ordering all CTEP supplied 
investigational agents.  The responsible investigator at each 
participating institution must be registered with CTEP, DCTD through 
an annual submission of FDA form 1572 (Statement of Investigator), 
Curriculum Vitae, Supplemental Investigator Data Form (IDF), and 
Financial Disclosure Form (FDF).  If there are several participating 
investigators at one institution, CTEP supplied investigational agents 
for the study should be ordered under the name of one lead 
investigator at that institution. 
Drug Ordering: 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 at 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 from 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 8:30 am and 4:30 pm (ET) or email 
PMBAfterHours@mail.nih.gov  anytime.  
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 NCI 
Investigator’s Handbook for Procedures for Drug Accountability and 
Storage. 
8.1.2 
Other Names  
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 
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).   
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8.1.3 
Classification  
Akt inhibitor 
8.1.4 
Mode of Action  
The PI3K-Akt pathway is activated downstream of EGFR, HER2, 
IGF1R, and cMet, and is a suspected driver of tumor progression in 
most cancers.  Overexpression or activating mutations in receptors 
tyrosine kinases, PI3K and Ras, inactivation of the tumor suppressor 
PTEN, or amplification or mutation of Akt can activate Akt protein 
kinase in most 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. 
8.1.5 
Storage and Stability  
Storage: Store intact bottles at room temperature, not to exceed 
300C. 
Stability:  Shelf life studies of MK-2206 are ongoing. 
8.1.6 
Dose Specifics  
MK-2206 200 mg per week, orally. MK-2206 should be taken 2 hours 
before or 2 hours after food. 
8.1.7 
How Supplied 
MK-2206 tablets are supplied by Merck and distributed by the DCTD, 
NCI. The 5-mg, 25-mg, and 200-mg tablets are film coated, packaged 
in HDPE bottles. The 5 mg and 25 mg bottles contain 10 and 20 
tablets, respectively. When inventory allows, the 5 mg and 25 mg 
bottles also contain 30 tablets each. The 200-mg 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®), 
croscarmellose sodium, and magnesium stearate.  
8.1.8 
Route of Administration 
Orally (2 hours before or after food). 
8.1.9 
Availability  
MK-2206 is an investigational agent (IND). MK-2206 tablets are 
supplied by Merck and distributed by the DCTD, NCI. 
Initial Drug Orders for Each Patient 
8.1.10 
Potential Drug Interactions 
MK-2206 is not a CYP3A4 inducer at clinically relevant 
concentrations.  MK-2206 is a substrate for P-glycoprotein (P-gp) 
mediated transport. 
8.1.11 
Side Effects  
Please refer to the CAEPR (Section 5.3). 
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Version Date: July 31, 2014 
 
NCI Update Date: July 2, 2013 
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8.1.12 
Nursing/Patient Implications  
1. MK-2206 should be taken 2 hours before or after food. 
2. If a patient vomits within 30 minutes of taking a dose of MK-2206, 
the dose should be replaced that day at the discretion of the 
investigator.  
3. A Patient Medication Calendar (Appendix IV) will be provided to 
the patient by the study coordinator at baseline and each 
subsequent visit, and a completed medication calendar should be 
returned by the patient at Day 1 of each cycle. 
4. ECG monitoring prior to and during MK2206 administration 
On day 1 of cycle 1, the patient will take the medication in the 
clinic.  
· 
Prior to drug administration obtain ONE ECG. 
· 
If QTc is ≤ 480 msec administer MK2206. Repeat ONE ECG 
within 4 to 10 hours after the treatment. 
· 
If QTc remains ≤ 480 msec one ECG will be performed once, 
at random, on day 1 of any subsequent treatment cycle. 
If the pre-treatment or post-treatment QTc value is greater than 480 
and less than 515 msec  
a. Measure serum phosphorous, potassium, magnesium, troponin, 
and calcium, and the patient must receive supplements to correct 
any low values.  
b. After correction of imbalances obtain three ECG’s at least 5 
minutes apart, so as to obtain an average pre-treatment QTc 
reading.  
c. Notify CTEP. Any final decisions concerning any dose 
modification/interruptions or patient discontinuing study drug 
permanently should be based on QTc calculations.  
d. If treatment is given, the drug must be taken in the office followed 
by three ECG’s at least 5 minutes apart within 4 to 10 hours after 
MK2206 administration to obtain a post-treatment average.  
e. A weekly ECG prior to dosing must be obtained at either the clinic 
or the local cardiologist to measure QTc.  
f. If QTc remains abnormal refer to a specialist if clinically indicated. 
g. At the end of the cycle QTc status should be re-evaluated.  
· 
if the QTc is less or equal than 480 msec monitor ECG only 
randomly.   
· 
if the QTc value is greater than 480 and less than 515 msec 
further discussion regarding continuation of the patient  on the 
same dose and in the study should be initiated between the 
investigator and CTEP. 
In general, there will be dose reductions for:  
· 
Multiple QTc equal or greater than 480  and less than 515 msec 
· 
Repeat dosing delays due to prolonged QTc intervals 
Rev. 4/12,  
       9/12 

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If QTc ≥ 515 msec  MK2206 will be discontinued 
All cardiac events should be treated as per the local standard of care 
and referred to a specialist by the investigator if clinically indicated. 
5. If a patient suffers from hyperglycemia it must be monitored 
closely. 
8.2 
Bicalutamide (Please refer to the package insert for more comprehensive 
information.) 
8.2.1 
Avaliability 
Bicalutamide is commercially available 
8.2.2 
Other Names 
Casodex®, a commercially available agent. 
8.2.3 
Chemical Name 
Propanamide, N-[4-cyano-3-(trifluromethyl)phenyl]-3-[4-
fluorophenyl)sulfonyl]-2-hydroxy-2-methyl-,(+/-) 
8.2.4 
Molecular Formula 
C18H14N2O4F4S 
8.2.5 
Mode of Action 
Competitive inhibitor of androgen binding to cytosolic androgen 
receptors. 
8.2.6 
How Supplied 
White, film-covered oral tablet containing 50 mg of bicalutamide. It is 
manufactured by AstraZeneca Pharmaceuticals in 50 mg tablets for 
oral administration and will not be provided by the study. 
8.2.7 
Storage 
Controlled room temperature, 20-25°C. 
8.2.8 
Dose Specifics 
50 mg/daily orally beginning Cycle 4 (week 13), continuously to the 
end of study (please see Section 5.1.1).  The tablet should be taken at 
approximately the same time every day.  
8.2.9 
Route of Administration 
Oral, may be taken with or without food. 
8.2.10 
Side Effects 
The most serious side-effect that has been associated with 
bicalutamide administration is severe liver injury, which has been 
reported in approximately 1% of patients in controlled clinical trials.  
Hepatotoxicity typically occurs within the first three to four months of 
continuous treatment. It is not known whether the regimen used in this 
trial can cause liver injury.  Transaminase levels will be drawn 
according to the table in Section 7.1.  Other common side-effects of 
bicalutamide overlap those of leuprolide acetate, including hot flashes, 
generalized pain, asthenia, constipation, diarrhea, nocturia, testicular 
atrophy, and gynecomastia. 

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9. 
Statistical Considerations 
9.1 
Study Design/Primary Endpoints 
The primary objective of this study is to compare the proportion of patients with 
undetectable PSA level (<0.2 ng/mL) at 44 weeks from study entry between two 
regimens (combination therapy-Arm B vs. bicalutamide monotherapy-Arm A). 
Patients randomized to Arm A will be observed for 12 weeks followed by a 32-
week bicalutamide treatment, while patients randomized to Arm B will be treated 
with MK-2206 for 12 weeks followed by a 32-week combination therapy with 
bicalutamide and MK-2206. The primary comparison will be an intention to treat 
analysis of all randomized patients. Although patients will be stratified based on 
Gleason score and prior hormonal therapy, no subgroup analyses are planned. 
We propose to equally randomize 52 patients to each arm, and a total of 104 
patients will be accrued to the study. The primary endpoint of this study is the 
proportion of patients with undetectable PSA level at 44 weeks from study entry. 
Patients who withdraw from the study prior to treatment completion will be 
considered non-responders. Based on preliminary data, we expect that 20% of 
patients will achieve undetectable PSA level at 44 weeks with bicalutamide 
monotherapy. With this design, we will have approximately 90% power with one-
sided alpha of 0.10 to detect a 25% absolute improvement in proportion of 
patients with undetectable PSA level at 44 weeks from 20% on Arm A to 45% on 
Arm B using Fisher’s exact test. Although it is unlikely to observe a large 
imbalance in dropout rates between two arms, the study will still have about 80% 
power to detect such an improvement with a 0% dropout rate in Arm A and a 
10% dropout rate in Arm B assuming the response rates are 45% and 20% on 
Arms B and A for patients with treatment completion, and 0% for those who 
withdraw before the end of treatment.  
9.2 
Secondary Endpoints 
Our secondary objectives include comparison of the proportion of patients that 
achieve a  
≥ 85% PSA decline at 44 weeks between the two arms, and evaluation of PSA 
response, time to PSA progression, time to PSA nadir, duration of PSA 
response, as well as PSA slope pre-treatment, during treatment, and off 
treatment. In addition, this study will evaluate whether Gleason score, and prior 
hormonal therapy have any effect on PSA response to treatment.  
Exact binomial confidence intervals will be used to describe the proportion of 
patients with ≥85% PSA decline at 44 weeks and the distribution of best PSA 
response (defined in Section 6.1). Patients who withdraw from the study prior to 
treatment completion will be considered non-responders for the analysis 
regarding 85% PSA decline at 44 weeks. Given 52 patients per arm, there will be 
88% power to test the proportion of patients with ≥85% PSA decline of 75% in 
the combination arm vs. 50% in bicalutamide monotherapy arm based on a 0.10 
level one-sided Fisher’s exact test.  
Duration of PSA response is defined as time from PSA response to PSA 
progression. Time to PSA progression, time to PSA nadir from registration, and 
duration of PSA response will be estimated on each arm and characterized using 
the method of Kaplan and Meier. Because patients with PSA rise greater than or 

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equal to 50% above baseline confirmed on a second measurement at least 2 
weeks later will be allowed to proceed to take bicalutamide before the end of 12 
weeks, the analysis of time to PSA nadir will be restricted to patients who do not 
start bicalutamide treatment early. Additionally, the percentage of patients who 
start bicaltamide treatment early in both arms will be reported. 
PSA slope will be assessed by multiple PSA values for four phases, prior to 
registration, from registration to starting bicalutamide treatment, from starting 
bicalutamide treatment until PSA nadir, and within a year after going off 
treatment; all values are required to be obtained from the same laboratory. Linear 
regression will be used to calculate PSA slope using natural log-transformed 
PSA values on the time of PSA measurements for each patient. This endpoint is 
exploratory and the analysis is descriptive in nature. 
As for the relationship between Gleason score, prior hormonal therapy and PSA 
response, we will fit a logistic regression to determine whether Gleason score 
and prior hormonal therapy have any effect on PSA response to treatment. 
Another important objective is to evaluate the safety and tolerability of MK-2206 
in this patient population. All patients who receive treatment, regardless of 
eligibility, will be evaluated for toxicity. The 90% confidence interval for the true 
probability of observing a toxicity of Grade 4 or higher on a given arm will be no 
wider than 25%. The probability of observing one or more toxicities on a given 
arm with a true rate of 5% is 93%. 
9.3 
Accrual 
We propose to equally randomize 52 patients to each arm, and a total of 104 
patients will be accrued to the study. According to previous ECOG studies with 
similar patient population, accrual is expected to be 6-8 patients per month and 
completed within 15 months.  
9.4 
Safety Monitoring 
Interim analyses of toxicity are performed twice yearly for all ECOG-ACRIN 
studies. Reports of these analyses are sent to the ECOG-ACRIN Principal 
Investigator or Senior Investigator at the participating institutions. Expedited 
reporting of certain adverse events is required, as described in Section 5.2. 

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9.5 
Gender and Ethnicity  
Based on previous data from E5803, the anticipated accrual in subgroups 
defined by gender and race for the present study is: 
Ethnic Category 
Gender 
Females 
Males 
Total 
Hispanic or Latino 
0 
3 
3 
Not Hispanic or Latino 
0 
101 
101 
Ethnic Category: Total of all subjects 
0 
104 
104 
Racial Category 
American Indian or Alaskan Native 
0 
0 
0 
Asian 
0 
0 
0 
Black or African American 
0 
11 
11 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
White 
0 
93 
93 
Racial Category: Total of all subjects 
0 
104 
104 
The accrual targets in individual cells are not large enough for definitive subgroup 
analyses. Therefore, overall accrual to the study will not be extended to meet 
individual subgroup accrual targets. 

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10. 
Correlative Studies 
Tissue specimens are requested for research. The research projects are currently 
undefined. Specimens are to be submitted only from patients who have answered “Yes” 
to “My specimens may be kept for use in future research to learn about, prevent, 
treat, or cure cancer.” 
10.1 
Sample Submissions 
Samples must be labeled with the protocol number, ECOG-ACRIN patient 
sequence number, date AND time of collection, and sample type (Plasma, urine, 
etc.).  
Questions about sample collection or submission are to be directed to the 
ECOG-ACRIN Pathology Coordinating Office-Reference Laboratory (PCORL), 
312- 503-3384. 
10.1.1 
Sample Preparations 
A. Tissue Specimens 
When a patient is randomized to receive protocol therapy, the 
submitting pathologist and clinical research associate should refer to 
Appendix II (Pathology Submission Guidelines). 
Required materials 
i. 
Forms: 
· 
Pathology Material Submission Form (#638 v04.2), Parts A & 
B completed. Please identify the clinical status of the 
submitted material (i.e., pretreatment as opposed to remission 
and relapse). 
· 
Copy of the surgical and pathology reports. 
· 
Reports of immunologic studies, if performed   
ii. Biological Material Submission:  
· 
Tumor tissue block: preferably from the prostatectomy 
specimen. If not available, submit block from the original 
biopsy 
· 
Normal tissue block 
NOTE: 
If a block is unavailable for submission, contact the 
ECOG-ACRIN PCORL to discuss alternative 
requirements. 
10.1.2 
Shipping Guidelines 
All submissions are to be logged into and tracked via the ECOG-
ACRIN Sample Tracking System (STS).  
Tissue blocks and the related reports and forms are to be submitted at 
ambient temperature within 1 month of patient registration.  
Ship to the ECOG-ACRIN PCORL: 
ECOG-ACRIN Pathology Coordinating Office-Reference 
Laboratory 
Ship Ambient  
To PCORL  
Rev. 6/14 

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Robert H. Lurie Comprehensive Cancer Center  
of Northwestern University Medical School 
Olson Pavilion - Room 8421 
710 North Fairbanks Court 
Chicago, IL 60611 
Tel: (312) 503-3384 
FAX: (312) 503-3385 
A shipping manifest generated from the STS is to be submitted with 
the samples. 
10.1.3 
Central Receiving Laboratories: Sample Processing and Routing 
Samples will be processed to maximize utilization of the specimens 
for research. E.g., processing of blocks will include, but not be limited 
to, the generation of tissue microarrays (TMAs) and the extraction of 
DNA and RNA.  
10.2 
ECOG-ACRIN Sample Tracking System 
It is required that all samples submitted on this trial be entered and tracked 
using the ECOG-ACRIN Sample Tracking System (STS). The software will allow 
the use of either 1) an ECOG-ACRIN user-name and password previously 
assigned (for those already using STS), or 2) a CTSU username and password.   
When you are ready to log the collection and/or shipment of the samples 
required for this study, please access the Sample Tracking System software by 
clicking https://webapps.ecog.org/Tst 
Important:  Any case reimbursements associated with specimen submissions 
may not be captured if specimens are not logged into STS. Additionally, please 
note that the STS software creates pop-up windows, so you will need to enable 
pop-ups within your web browser while using the software.  A user manual and 
interactive demo are available by clicking this link: 
http://www.ecog.org/general/stsinfo.html Please take a moment to familiarize 
yourself with the software prior to using the system. 
An STS generated shipping manifest should be shipped with all specimen 
submissions. 
Please direct your questions or comments pertaining to the STS to 
ecog.tst@jimmy.harvard.edu 
Study Specific Notes 
If STS is unavailable at time of shipment, specimens are to be submitted with the 
appropriate documentation outlined above and notify the PCORL (312-503-3384) 
of the shipment. Retro actively enter all specimen collection and shipping 
information when STS is available. 
10.3 
Banking  
The specimens collected for this study will be forwarded and retained at the 
ECOG-ACRIN Pathology Coordinating Office-References Laboratory (PCORL) 
for possible use in ECOG-ACRIN approved future studies. If future use is denied 
or withdrawn by the patient, the samples will be removed from consideration for 
use in any future study. 

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10.4 
Sample Inventory Submission Guidelines  
Inventories of all samples collected, aliquoted, and used for any approved 
laboratory research studies will be submitted electronically to the ECOG-ACRIN 
Operations Office – Boston on a monthly basis. 

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11. 
Records to Be Kept 
Please refer to the E2809 Forms Packet for the forms submission schedule and copies 
of all forms. The E2809 Forms Packet may be downloaded by accessing the ECOG 
World Wide Web Home Page (http://www.ecog.org). Forms must be submitted to the 
ECOG-ACRIN Operations Office – Boston, FSTRF, 900 Commonwealth Avenue, 
Boston, MA 02215 (ATTN: DATA). 
This study is being conducted under an IND. Cumulative CDUS data will be submitted 
quarterly from the ECOG-ACRIN Operations Office – Boston by electronic means. 
11.1 
Records Retention  
FDA regulations (21 CFR 312.62) require clinical investigators to retain all trial-
related documentation, including source documents, long enough to allow the 
sponsor to use the data to support marketing applications. 
This study is being conducted under an IND. All records pertaining to the trial 
(including source documents) must be maintained for: 
· 
two years after the FDA approves the marketing application, or 
· 
two years after the FDA disapproves the application for the indication being 
studied, or 
· 
two years after the FDA is notified by the sponsor of the discontinuation of 
trials and that an application will not be submitted.  
Please contact the ECOG-ACRIN Operations Office – Boston prior to destroying 
any source documents. 
12. 
Patient Consent and Peer Judgment 
Current FDA, NCI, state, federal and institutional regulations concerning informed 
consent will be followed. 
13. 
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Majumder PK, Yeh JJ, George DJ, Febbo PG, Kum J, Xue Q, et al. Prostate 
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Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, et al. PTEN, a putative 
protein tyrosine phosphatase gene mutated in human brain, breast, and prostate 
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Mulholland DJ, Dedhar S, Wu H, Nelson CC. PTEN and GSK3beta: key 
regulators of progression to androgen-independent prostate cancer. Oncogene. 
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Yoshimoto M, cunha IW, Coudry RA, al. e. FISH analysis of 107 prostate cancers 
shows that PTEN genomic deletion is associated with poor clincal outcome Br J 
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McMenamin ME, Soung P, Perera S, Kaplna I, Loda M, WR S. Loss od PTEN 
expression in paraffin embedded primary prostate  cancer correlates with high 
Gleason score and advanced stage. Cancer research. 1999;59:4291-6. 
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Suzuki H, Freije D, Nusskern DR, Okami K, Cairns P, Sidransky D, et al. Interfocal 
heterogeneity of PTEN/MMAC1 gene alterations in multiple metastatic prostate 
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64. 
Bertram J, Peacock JW, Fazli L, al. e. Loss of PTEN is associatyed with 
progression to androgen independence. The Prostate. 2005;66:895-902. 
65. 
Edwards J, Krishna NS, Witton CJ, Bartlett JM. Gene amplifications associated 
with the development of hormone-resistant prostate cancer. Clin Cancer Res. 
2003 Nov 1;9(14):5271-81. 
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Stern D. More than a marker...phosphorylated Akt in prostate carcinoma. Clin 
Cancer Res. 2004;10:6407-10. 
67. 
Malik S, Brattain M, Ghosh P, Troyer D, Prihoda T, Bedolla R, et al. 
Immunohistochemical demonstration of phospho-Akt in high Gleason grade 
prostate cancer. Clin Cancer Res. 2002;8(4):1168-71. 
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Ayala G, Thompson T, Yang G, Frolov A, Li R, Scardino P, et al. High levels of 
phosphorylated form of Akt-1 in prostate cancer and non-neoplastic prostate 
tissues are strong predictors of biochemical recurrence. Clin Cancer Res. 2004 
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Li R, Dai H, Wheeler TM, Sayeeduddin M, Scardino PT, Frolov A, et al. Prognostic 
value of Akt-1 in human prostate cancer: a computerized quantitative assessment 
with quantum dot technology. Clin Cancer Res. 2009 May 15;15(10):3568-73. 
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Manin M, Baron S, Goossens K, Beaudoin C, Jean C, Veyssiere G, et al. 
Androgen receptor expression is regulated by the phosphoinositide 3-kinase/Akt 
pathway in normal and tumoral epithelial cells. Biochem J. 2002 Sep 15;366(Pt 
3):729-36. 
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Wen Y, Hu M, Makino K, Spohn B, Bartholomeusz G, Yan D, et al. HER-2/neu 
promotes androgen-independent survival and growth of prostate cancer cells 
through the Akt pathway. Cancer research. 2000;60(24):6841-5. 
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Nan B, Snabboon T, Unni E, Yuan X-J, Whang Y, Marcelli M. The PTEN tumor 
suppressor is a negative modulator of androgen receptor transcriptional activity. J 
Mol Endocrinol. 2003;31(1):169-83. 
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Ellerby LM, Hackam AS, Propp SS, Ellerby HM, Rabizadeh S, Cashman NR, et al. 
Kennedy's disease: caspase cleavage of the androgen receptor is a crucial event 
in cytotoxicity. J Neurochem. 1999 Jan;72(1):185-95. 

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Cancer Research Group 
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74. 
Sharma M, Chuang W, Sun Z. Phosphatidylinositol 3-kinase/Akt stimulates 
androgen pathway through GSK3beta inhibition and nuclear beta-catenin 
accumulation. The Journal of biological chemistry. 2002;277(34):30935-41. 
75. 
Graff JR, Konicek BW, McNulty AM, Wang Z, Houck K, Allen S, et al. Increased 
AKT activity contributes to prostate cancer progression by dramatically 
accelerating prostate tumor growth and diminishing p27Kip1 expression. The 
Journal of biological chemistry. 2000 Aug 11;275(32):24500-5. 
76. 
Cohen MB, Rokhlin OW. Mechanisms of prostate cancer cell survival after 
inhibition of AR expression. J Cell Biochem. 2009 Feb 15;106(3):363-71. 
77. 
Garcia JA, A. M. Reuther, A. J. Stephenson, R. Dreicer, E. Klein, C. Magi-
Galluzzi. mTOR pathway in prostate cancer: Immunohistochemical expression on 
tissue microarrays. . Genitourinary Cancers Symposium, Abs#32 
2008;Genitourinary Cancers Symposium, Abs#32  
78. 
Xu Y, Chen SY, Ross KN, Balk SP. Androgens induce prostate cancer cell 
proliferation through mammalian target of rapamycin activation and post-
transcriptional increases in cyclin D proteins. Cancer research. 2006 Aug 
1;66(15):7783-92. 
79. 
Thomas G, Speicher L, Reiter R, al. e. Demonstration that temsirolimus 
preferentially inhibits the mTOR pathway in the tumors of prostate cancer patients 
with PTEN deficiences AACR-NCI-EORTC International Conference. 2005. 
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Amato R.J, Jac J, Mohammed T, S S. Pilot study of rapamycin in patients with 
castration resistant prostate cancer.  Clin Genitourin Cancer 2008:97-102. 
81. 
Craft N, Shostak, Y., Carey, M., Sawyers, C.L. A mechanism for hormone-
independent prostate cancer through the modulation of androgen receptor 
signaling by the HER-2/neu tyrosine kinase. Nature Medicine. 1999;5(3):280-5. 
82. 
Heinlein CA, C C. Androgen receptor coregulators: an overview. Endocr Rev. 
2002;23(2):175-200. 
83. 
Craft  N, C. S. Mechanistic concepts in androgen-dependence of prostate cancer 
Cancer and metastasis review. 1999;5:421-7. 
84. 
Wu JD, Haugk K, Coleman I, Woodke L, Vessella R, Nelson P, et al. Combined In 
vivo Effect of A12, a Type 1 Insulin-Like Growth Factor Receptor Antibody, and 
Docetaxel against Prostate Cancer Tumors. Clin Cancer Res. 2006 Oct 
15;12(20):6153-60. 
85. 
Lewis JE KB, McNulty AM, Parsons S, Lynch RL, Graff JR Enzastaurin 
(LY317615.HCl) reduces Androgen Receptor (AR) expression in hormone-
dependent and independent prostate cancers. Proc AACR. 2007 January, 2007. 
86. 
Zelivianski S, Spellman M, M K, Kakitelashvilli V, Zhou XW, Lugo E, et al. ERK 
ihibitor PD98059 enhances docetaxel-induced apoptosis of androgen-
independent human prostate cancer cells. . Int J of Can. 2003;107:478-85. 
87. 
Ghosh PM, Malik SN, Bedolla RG, Wang Y, Mikhailova M, Prihoda TJ, et al. 
Signal transduction pathways in androgen-dependent and -independent prostate 
cancer cell proliferation. Endocr Relat Cancer. 2005 March 1, 2005;12(1):119-34. 

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88. 
Ferrari AC, Wang L, Liu X. Androgen receptor (AR) modulation strategies for 
recurrent prostate cancer (PC) without androgen suppression.  2006 ASCO 
Annual Meeting Proceedings Part I  2006; Atlanta, GA; 2006. p. Abstract #4657. 
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Festuccia C, Gravina GL, Angelucci A, Millimaggi D, Muzi P, Vicentini C, et al. 
Additive antitumor effects of the epidermal growth factor receptor tyrosine kinase 
inhibitor, gefitinib (Iressa), and the nonsteroidal antiandrogen, bicalutamide 
(Casodex), in prostate cancer cells in vitro. International journal of cancer. 2005 
Jul 1;115(4):630-40. 
90. 
Schayowitz A, Sabnis G, Njar VC, Brodie AM. Synergistic effect of a novel 
antiandrogen, VN/124-1, and signal transduction inhibitors in prostate cancer 
progression to hormone independence in vitro. Mol Cancer Ther. 2008 
Jan;7(1):121-32. 
91. 
Zhang W, Zhu J, Efferson CL, Ware C, Tammam J, Angagaw M, et al. Inhibition of 
tumor growth progression by antiandrogens and mTOR inhibitor in a Pten-
deficient mouse model of prostate cancer. Cancer research. 2009 Sep 
15;69(18):7466-72. 
92. 
Soloway MS, Schellhammer PF, Smith JAJ, Chodak GW, Vogelzang NJ, 
Kennealey GT. Bicalutamide in the treatment of advaned prostatic carcinoma: a 
phase II noncomparative multicenter trial evaluating safety, efficacy and long-term 
endocrine effects of monotherapy. J Urol. 1995;154:2110-4. 
93. 
Kaisary AV, Tyrrell CJ, Beacock C, Lunglmayr G, Debruyne F. A randomised 
comparison of monotherapy with Casodex 50 mg daily and castration in the 
treatment of metastatic prostate carcinoma. Casodex Study Group. Eur Urol. 
1995;28(3):215-22. 
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Iversen P, Tveter K, Varenhorst E. Randomised study of Casodex 50 mg 
monotherapy vs orchidectomy in the treatment of metastatic prostate cancer. The 
Scandinavian Casodex Cooperative Group. Scand J Urol Nephrol. 1996;30:93-8. 
95. 
Kolvenbag GJ, Blackledge GR, Gotting-Smith K. Bicalutamide (Casodex) in the 
treatment of prostate cancer: history of clinical development. The Prostate. 1998 
Jan 1;34(1):61-72. 
96. 
Backledge G. High-dose bicalutamide monotherapy for the treatment of prostate 
cancer. Urology. 1996;47(Suppl.1A):44-7. 
97. 
 Iversen P, Tryyell C, Kaisary A, Anderson J, van Poppel E, Tammela T, et al. 
Bicalutamide monotherapy compared with castration in patients with 
nonmetastatic locally advanced prostate cancer: 6.3 years of followup. Journal of 
Urology. 2000;164:1579-82. 
98. 
Tay M-H, Kaufman D, Regan M, Leibowitz S, George D, Febbo D, et al. 
Finasteride and bicalutamide as primary hormonal therapy in patients with 
advanced adenocarcinoma of the prostate Annals of Oncology. 2004;15:974-8. 
99. 
Picus J, Halabi E, Small E, Hussain A, Phillips G, Kaplan N, et al. Efficacy of 
peripheral androgen blockade on prostate cancer. Results of CALGB 9782. . Proc 
Am Soc Clin Onc   2006:234s. 
100. Brufsky A, Fontaine-Rothe P, Berlane K, Rieker P, Jiroutek M, Kaplan I, et al. 
Finasteride and flutamide as potency-sparing androgen-ablative therapy for 
advanced adenocarcinoma of the prostate. Urology. 1997;49(6):913-20. 

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101. Stewart AJ, Scher HI, Chen MH, McLeod DG, Carroll PR, Moul JW, et al. 
Prostate-specific antigen nadir and cancer-specific mortality following hormonal 
therapy for prostate-specific antigen failure. J Clin Oncol. 2005 Sep 
20;23(27):6556-60. 
102. Beekman K, Morris M, Slovin S, Heller G, Wilton A, Bianco F, Jr., et al. Androgen 
deprivation for minimal metastatic disease: threshold for achieving undetectable 
prostate-specific antigen. Urology. 2005 May;65(5):947-52. 
103. Hachiya T, Minei S, Kobayashi K, Ishida H, K O. Prediction of organ-confined 
disease by prostate-specific antigen nadir after neoadjuvant therapy. Int J Urol. 
2000;7(11):393-401. 
104. Hussain M, Tangen CM, Higano C, Schelhammer PF, Faulkner J, Crawford ED, et 
al. Absolute prostate-specific antigen value after androgen deprivation is a strong 
independent predictor of survival in new metastatic prostate cancer: data from 
Southwest Oncology Group Trial 9346 (INT-0162). J Clin Oncol. 2006 Aug 
20;24(24):3984-90. 
105. Baselga J. Targeting tyrosine kinases in cancer: the second wave. Science (New 
York, NY. 2006 May 26;312(5777):1175-8. 
106. Varambally S, Yu J, Laxman B, Rhodes DR, Mehra R, Tomlins SA, et al. 
Integrative genomic and proteomic analysis of prostate cancer reveals signatures 
of metastatic progression. Cancer Cell. 2005 Nov;8(5):393-406. 
107. Mitchell PS, Parkin RK, Kroh EM, Fritz BR, Wyman SK, Pogosova-Agadjanyan 
EL, et al. Circulating microRNAs as stable blood-based markers for cancer 
detection. Proceedings of the National Academy of Sciences of the United States 
of America. 2008 Jul 29;105(30):10513-8. 
108. Scher HI, M. E, D'Amico AV, Halabi S, Small EJ, Morris M, et al. Eligibility and 
outcomes reporting guidelines for clinical trials for patients in the state of a rising 
prostate-specific antigen: recommendations formthe prostate-specific antigen 
working group. J Clin Oncol. 2004;22(3):537-56. 
109. D'Amico AV, Cote K, Laffredo M, A. R, Schultz D. Determinants of prostate 
cancer-specific survival after radiation therapy for patients with clinically localized 
prostate cancer. J Clin Onc. 2002;23(23):4567-73. 
110. D'Amico AV, Moul J, Carroll PR, Sun L, Lubeck D, Chen MH. Prostate specific 
antigen doubling time as a surrogate end point for prostate cancer specific 
mortality following radical prostatectomy or radiation therapy. J Urol. 2004 
Dec;172(5 Pt 2):S42-6; discussion S6-7. 
111. Kim-Sing C, Pickles T. Intervention after PSA failure: Examination of intervention 
time and subsequent outcomes from a prospective patient database. International 
Journal of Radiation Oncology*Biology*Physics. 2004;60(2):463. 
112. Hanlon AL, Horwitz EM, Hanks GE, Pollack A. Short-term androgen deprivation 
and PSA doubling time: their association and relationship to disease progression 
after radiation therapy for prostate cancer. International Journal of Radiation 
Oncology*Biology*Physics. 2004;58(1):43. 
113. Freedland SJ, Humphreys EB, Mangold LA, Eisenberger M, Dorey FJ, Walsh PC, 
et al. Risk of Prostate Cancer-Specific Mortality Following Biochemical 
Recurrence After Radical Prostatectomy. JAMA. 2005 July 27, 2005;294(4):433-9. 

ECOG-ACRIN 
E2809 
Cancer Research Group 
Version Date: July 31, 2014 
 
NCI Update Date: July 2, 2013 
74 
Androgen Receptor Modulation 
Phase II, Randomized Study of MK-2206 - Bicalutamide Combination in Patients With 
Rising PSA at High-Risk of Progression After Primary Therapy 
 
Version Date: December 28, 2012 
Appendix I 
 
Informed Consent Template for Cancer Treatment Trials (English Language) 
[Deleted in Addendum #5] 
INFORMED CONSENT INTENTIONALLY REMOVED FROM 
PROTOCOL DOCUMENT 
Appendix I was removed from the protocol document in Addendum #5 and is posted as a 
separate document on the ECOG website. This was removed from the protocol to comply with 
NCI formatting guidelines. 

ECOG-ACRIN 
E2809 
Cancer Research Group 
Version Date: July 31, 2014 
 
NCI Update Date: July 2, 2013 
75 
Androgen Receptor Modulation 
Phase II, Randomized Study of MK-2206 - Bicalutamide Combination in Patients With 
Rising PSA at High-Risk of Progression After Primary Therapy 
 
Appendix II 
 
Pathology Submission Guidelines 
The following items are included in Appendix II: 
1. 
Guidelines for Submission of Pathology Materials  
(instructional sheet for Clinical Research Associates [CRAs]) 
2. 
Instructional memo to submitting pathologists 
3. 
List of Required Materials for E2809 
4. 
Pathology Submission Form (#638 v04.2) 
 

ECOG-ACRIN 
E2809 
Cancer Research Group 
Version Date: July 31, 2014 
 
NCI Update Date: July 2, 2013 
76 
Guidelines for Submission of Pathology Materials 
The following items should always be included when submitting pathology materials 
to the ECOG-ACRIN Pathology Coordinating Office: 
· 
Institutional Surgical Pathology Report 
· 
Pathology materials (see attached List of Required Material) 
· 
Pathology Material Submission Form (#638 v04.2) 
Instructions: 
1. Place the Patient ID label provided by the ECOG-ACRIN Operations Office – Boston 
in Part A of the Pathology Material Submission Form. 
 
If a label is not available, TYPE or PRINT the following information in Part A of the 
form: 
· 
Patient's name (last, first) 
· 
Protocol number 
· 
Protocol case number (the patient's ECOG-ACRIN sequence number; for 
intergroup studies, include both the ECOG-ACRIN and other group's sequence 
numbers) 
· 
Patient's hospital number 
· 
Institution 
· 
Affiliate (if appropriate) 
2. Complete blank areas of the pathologist's instructional memo and forward it, along 
with the List of Required Material and the Pathology Material Submission Form, to 
the appropriate pathologist.  
3. The pathologist should return the required pathology samples and surgical pathology 
reports, along with the completed Pathology Material Submission Form (#638 v04.2) 
(Part B completed). If any other reports are required, they should be obtained from 
the appropriate department at this time. 
4. Keep a copy of the Pathology Material Submission Form (#638 v04.2) for your 
records.  (The original should be sent to the PCO.) 
5. Double-check that ALL required forms, reports and pathology samples are included 
in the package to the Pathology Coordinating Office. (See appropriate List of 
Required Material.) 
Pathology specimens submitted WILL NOT be processed by the Pathology 
Coordinating Office until all necessary items are received. 
Mail pathology materials to: 
ECOG-ACRIN Pathology Coordinating Office 
Robert H. Lurie Comprehensive Cancer Center  
of Northwestern University Medical School 
Olson Pavilion - Room 8421 
710 North Fairbanks Court 
Chicago, IL  60611 
If you have any questions concerning the above instructions or if you anticipate any 
problems in meeting the pathology material submission deadline of one month, contact 

ECOG-ACRIN 
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Version Date: July 31, 2014 
 
NCI Update Date: July 2, 2013 
77 
the Pathology Coordinator at the ECOG-ACRIN Pathology Coordinating Office by 
telephone (312) 503-3384 or by fax (312) 503-3385.

ECOG-ACRIN 
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Cancer Research Group 
Version Date: July 31, 2014 
 
NCI Update Date: July 2, 2013 
78 
List of Required Material 
E2809:  Androgen Receptor Modulation Phase II, Randomized Study of MK-2206 - 
Bicalutamide Combination in Patients With Rising PSA at High-Risk of 
Progression After Primary Therapy 
Pre-Treatment 
1. Pathology Material Submission Form (#638 v04.2) – Parts A & B completed. [or 
appropriate pathology submission form]   
2. Institutional pathology report (must be included with EVERY pathology 
submission). 
3. Institutional surgical report 
4. Biological materials. 
· 
One Tumor tissue block: preferably from the prostatectomy specimen. If not 
available, submit block from the original biopsy. 
· 
One normal tissue or block. 
NOTE: 
If a block is unavailable for submission, contact the ECOG-ACRIN PCO to 
discuss submission requirements. 
 

 
79 
MEMORANDUM 
TO:  
_____________________________________ 
 
(Submitting Pathologist) 
FROM: 
Stanley Hamilton, M.D., Chair 
 
ECOG-ACRIN Laboratory Science and Pathology Committee 
DATE:  
_____________________________________ 
SUBJECT: 
Submission of Pathology Materials for E2809: Androgen Receptor 
Modulation Phase II, Randomized Study of Patients With Rising PSA 
at High-Risk of Progression After Primary Therapy to Assess the 
Clinical and Molecular Efficacy of the MK-2206 - Bicalutamide 
Combination to Suppress the Androgen Receptor Without 
Testosterone Ablation 
 
The patient named on the attached Pathology Material Submission Form (# 638v 04.2) 
has been entered onto an ECOG-ACRIN protocol by 
______________________________ (ECOG-ACRIN Investigator).  This protocol 
requires the submission of pathology materials for laboratory studies. 
Please complete PART B of the Submission Form. Keep a copy for your records and 
return the completed Submission Form, the surgical pathology report(s), the slides 
and/or blocks and any other required material (see List of Required Material) to the 
Clinical Research Associate (CRA).  The CRA will forward all required pathology 
material to the ECOG-ACRIN Pathology Coordinating Office. 
Blocks and slides submitted for this study will be retained at the ECOG-ACRIN Central 
Repository for future studies. Paraffin blocks will be returned upon written request for 
purposes of patient management only. 
Please note: Since blocks are being used for laboratory studies, in some cases the 
material may be depleted, and, therefore, the block may not be returned. 
If you have any questions regarding this request, please contact the Pathology 
Coordinating Office at (312) 503-3384 or FAX (312) 503-3385. 
The ECOG-ACRIN CRA at your institution is: 
Name: ___________________________________  
Address: _________________________________  
Phone: __________________________________  
 
Thank you. 

Form No. 638 v04.2 
ECOG DIAGNOSTIC PATHOLOGY MATERIAL SUBMISSION FORM 
80 
Instructions: 
This form is a required part of pathology submission.  Please complete and submit along with 
all pathology material and corresponding pathology reports requested by the protocol.  See list of 
required materials as specified in EACH protocol. 
ECOG PCO-RL IS FULLY- COMPLIANT WITH DHHS, HIPAA, AND OHRP REGULATIONS 
Tel. 312-503-3384
 
Fax 312-503-3385 
PART A:  To Be Completed By Data Manager/CRA 
DO NOT USE INITIALS – Submit Patient’s FULL Name 
 
(The Patient has authorized the use of PHI.) 
Date sample sent to ECOG ______/______/_______ (M,D,Y) 
 
Patient’s Name: 
Data Manager _______________________________________  
 
Last _______________________ 
First ____________________  
Address  ___________________________________________  
 
ECOG Prot. No. _________  ECOG Patient Seq. No. ________  
 __________________________________________________  
 
Participating Group 
Prot. No. _______________  
Participating Group 
Patient ID No. ________________  
Telephone No. (          ) _______________________________  
 
Group __________ 
Institution _________ 
PI _____________  
Fax No. (          ) _____________________________________  
 
Step No. ________ 
Affiliate _________  
Email address  ______________________________________  
 
ECOG Parent Prot. No. ________  
Seq. No. ______________  
PART B: 
TO BE COMPLETED BY DATA MANAGER/CRA AND SUBMITTING PATHOLOGIST 
 
 
 
 
 
 
 
PCO-RL Use Only 
Complete for 
Slides/Vials 
Status* 
(See Below) 
Date Specimen 
Collected (M/D/Y) Disease Site 
Number of 
Slides/Vials 
Specimen ID  
Numbers 
Type of 
Stain 
PCO ID 
Numbers 
 
 
/        / 
 
 
 
 
 
 
 
/        / 
 
 
 
 
 
Complete for 
Blocks/Punch 
Status* 
(See Below) 
Date Specimen 
Collected (M/D/Y) Disease Site 
Number of 
Blocks/Punch 
Specimen ID  
Numbers 
Fixative 
PCO ID 
Numbers 
 
 
/        / 
 
 
 
 
 
 
 
/        / 
 
 
 
 
 
*Status: Please identify the clinical status of the sample.  
List all that apply: 
 
 
1. Original diagnostic material 
5. Post-surgery biopsy/tissue 
 
Submitting Pathologist _____________________ 
2. AML/MDS diagnosis 
6. Relapse/recurrence 
 
Telephone No. (          ) ____________________ 
3. Pre-protocol treatment 
biopsy/tissue 
7. Remission/response 
 
 
Address  ________________________________ 
4. Post-protocol treatment 
biopsy/tissue 
8. Other, specify: ______________  
 
  _________________________  
 
 _______________________________________ 
Did the patient consent to participate in the storage of samples for future research? 
Yes 
No 
MATERIAL RETURN (All materials will be retained by the ECOG PCO unless return is requested here.) 
Does the submitting institution’s policy require the return of any submitted material (blocks, H&E slides, etc.)? 
Yes 
No 
If so, please indicate which materials must be returned ______________________________________________________________  
All materials will be returned to the submitting pathologist unless an alternate address is indicated here ______________________  
If materials were not able to be submitted for this protocol and its correlative studies, please circle the 
reason for non-submission. Attach a formal letter referencing regulations, policy, and/or other explanation. If 
possible, include a copy of the policy.  
Federal/State Regulations ____  Hospital/Institutional Policy _____ Insufficient Tissue _____  Other ______  (Specify) _________  
Pathologist or Investigator’s Signature ______________________________________________ 
(PCO-RL Use Only) 
PV  _________________________  
PART C: 
ECOG PATHOLOGY COORDINATING OFFICE USE ONLY 
Date Sample Received at PCO ____/____/____ 
Date Sent to Reviewer ____/____/____ 
Date Sent to PI/Central Lab ____/____/_____ 
Site Compliance % _____________ 
Name of Reviewer __________________ PI/Central Lab _________________________  
PCO Comments: _____________________________________________________________________  
Staff Init. _____________  
Investigator:  Keep a copy for your files and submit original form to the destination specified in protocol. 
2/05 

ECOG-ACRIN 
E2809 
Cancer Research Group 
Version Date: July 31, 2014 
 
NCI Update Date: July 2, 2013 
81 
Androgen Receptor Modulation 
Phase II, Randomized Study of MK-2206 - Bicalutamide Combination in Patients With 
Rising PSA at High-Risk of Progression After Primary Therapy 
 
Appendix III 
 
Patient Thank You Letter 
We ask that the physician use the template contained in this appendix to prepare a letter 
thanking the patient  for enrolling in this trial. The template is intended as a guide and 
can be downloaded from the ECOG web site at http://www.ecog.org. As this is a 
personal letter, physicians may elect to further tailor the text to their situation. 
This small gesture is a part of a broader program being undertaken by ECOG-ACRIN 
and the NCI to increase awareness of the importance of clinical trials and improve 
accrual and follow-through. We appreciate your help in this effort. 
 ________________________________________________________________________  
 
[PATIENT NAME] 
[DATE] 
[PATIENT ADDRESS] 
 
 
Dear [PATIENT SALUTATION], 
 
Thank you for agreeing to take part in this important research study.  Many questions 
remain unanswered in cancer. With the help of people like you who participate in clinical 
trials, we will achieve our goal of effectively treating and ultimately curing cancer. 
We believe you will receive high quality, complete care. Your physician and research 
staff will maintain very close contact with you. This is important so as to allow your 
physician to provide you with the best care while learning as much as possible to help 
you and other patients. 
On behalf of [INSTITUTION] and the ECOG-ACRIN Cancer Research Group, we thank 
you again and look forward to helping you. 
 
 
Sincerely, 
 
 
 
 
[PHYSICIAN NAME] 
 
 

ECOG-ACRIN 
E2809 
Cancer Research Group 
Version Date: July 31, 2014 
 
NCI Update Date: July 2, 2013 
82 
Androgen Receptor Modulation 
Phase II, Randomized Study of MK-2206 - Bicalutamide Combination in Patients With 
Rising PSA at High-Risk of Progression After Primary Therapy 
 
Appendix IV 
 
Patient Medication Calendar (Pill Diary) 
 
Patient Name: ________________________________________________________________ 
ECOG-ACRIN Patient Sequence Number: ________________________ 
Patient's Treatment Arm (e.g., "A"): _________ 
Patient's Initials: ____________ 
Protocol Number: E2809 
Cycle # ______  
Start Day of Week: ___________________________________ 
Start Date (e.g., 01/01/09) for first dose of this cycle: _______________________ 
NOTE: 
A cycle is 28 days (4 weeks) 
Directions for Arm A: 
1.  Unless your doctor decides to begin bicalutamide early, for the first three cycles of the study, 
you will not take any study medication and you are not responsible for submitting a patient 
pill diary. 
2.  Unless your doctor decides to begin bicalutamide early, starting with Cycle 4, for each cycle, 
take 1 Bicalutamide tablet (50 mg) orally once daily continuously through Cycle 11.   
3.  After Cycle 11, your doctor may advise you to stop and come off-treatment or continue on 
treatment through Cycle 18. 
4.  For each Cycle that you end up taking bicalutamide you should complete an ARM A Patient 
Medication Calendar (Pill Diary) appropriately based on the days you actually took 
medication during the cycle. 
5.  If a dose is forgotten do not take it at a later time. Skip that dose and note in the calendar 
that the dose was missed. 
Directions for Arm B: 
1.  For cycles 1-3, take 200 mg of MK-2206 by mouth each week. You should take the 
medication at about the same time 2 hours before or after meals. Your doctor may also 
decide to start bicalutamide early. 
2. Unless started early, starting with Cycle 4, you will take 1 Bicalutamide tablet (50 mg) orally 
every day in addition to continuing the weekly MK-2206 treatment. You will continue this 
combined therapy through Cycle 11. 
3.  After Cycle 11, your doctor may advise you to stop and come off-treatment or continue on 
the combined treatment through Cycle 18. 
4.  For each Cycle that you end up taking either MK-2206 or the combination of MK-2206 and 
bicalutamide you should complete an ARM B Patient Medication Calendar (Pill Diary) 
appropriately based on the days you actually took medication during the cycle. 

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5.  If a dose is forgotten do not take it at a later time. Skip that dose and note in the calendar 
that the dose was missed. 
Note the number of pills you take each day. If you develop any side effects, please record 
side effects, the date, and anything you would like to tell the doctor in the comments section of 
your calendar.  
Bring your bottles and any unused pills along with your completed calendar/diary to your 
next appointment. 
Signature of Patient: ____________________________________ Date: ________________  
 
 

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E2809 Patient Medication Calendar (Diary) – ARM A 
Patient ID: ___________ 
 
 
 
Cycle #: ______ 
Cycle Day 
Day of 
Week 
Date 
Bicalutamide 
(Casodex®) 
(50 mg) 
Comments 
Example: 
Mon. 
1/2/10 
1 tablet/time taken 
Side effects/other medication taken 
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 
 
 
 
 
 

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NCI Update Date: July 2, 2013 
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E2809 Patient Medication Calendar (Diary) – ARM B 
Patient ID: ___________ 
 
 
 
 
Cycle #: ______ 
Cycle 
Day 
Day of 
Week 
Date 
MK-2206 
(5 mg) 
MK-2206 
(25 mg) 
MK-2206 
(200 mg) 
Bicalutamide 
(Casodex®) 
(50 mg) 
Comments 
Ex: 
Mon. 
1/2/10 
# tablet/time taken 
1 tablet/time taken 
Side effects/other 
medication taken 
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 
 
 
 
 
 
 
 
 

ECOG-ACRIN 
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Cancer Research Group 
Version Date: July 31, 2014 
 
NCI Update Date: July 2, 2013 
86 
Androgen Receptor Modulation 
Phase II, Randomized Study of MK-2206 - Bicalutamide Combination in Patients With 
Rising PSA at High-Risk of Progression After Primary Therapy 
 
Appendix V 
 
Cooperative Research and Development Agreement (CRADA) 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis.  Therefore, the following obligations/guidelines, in addition to the 
provisions in the Intellectual Property Option to Collaborators 
(http://ctep.cancer.gov/industry/ipo.html) contained within the terms of award, apply to the use of 
the Agent(s) in this study: 
1. 
Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study.  
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and 
shall be maintained as such by the investigators. The protocol documents for studies 
utilizing investigational Agents contain confidential information and should not be shared 
or distributed without the permission of the NCI.  If a copy of this protocol is requested by a 
patient or patient’s family member participating on the study, the individual should sign a 
confidentiality agreement. A suitable model agreement can be downloaded from: 
http://ctep.cancer.gov. 
2. 
For a clinical protocol where there is an investigational Agent used in combination with 
(an)other investigational Agent(s), each the subject of different collaborative agreements , 
the access to and use of data by each Collaborator shall be as follows (data pertaining to 
such combination use shall hereinafter be 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. 

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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: 
Regulatory Affairs Branch, CTEP, DCTD, NCI 
Executive Plaza North, Suite 7111 
Bethesda, Maryland  20892 
FAX 301-402-1584 
Email: anshers@mail.nih.gov  
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator=s confidential/ 
proprietary information. 

ECOG-ACRIN 
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Cancer Research Group 
Version Date: July 31, 2014 
 
NCI Update Date: July 2, 2013 
88 
Androgen Receptor Modulation 
Phase II, Randomized Study of MK-2206 - Bicalutamide Combination in Patients With 
Rising PSA at High-Risk of Progression After Primary Therapy 
 
Appendix VI 
 
List of CYP3A4 Inhibitors and Inducers 
CYP3A4 Inhibitors 
Amiodarone 
Aprepitant 
Atazanavir 
Azithromycin 
Bupropion 
Cerivastatin 
Chloramphenicol 
Chlorpromazine 
Chlorpheniramine  
Chlorzoxazone 
Cimetidine 
Ciprofloxacin 
Clarithromycin 
Clemastine 
Clofazimine 
Clotrimazole 
Cocaine 
Conivaptan 
Cyclophosphamide 
Cyclosporine 
Danazol 
Dasatinib (1) 
Delavirdine 
Dexmedetomidine 
 
Diclofenac 
Diethyl-dithiocarbamate 
Dihydroergotamine 
Diltiazem 
Diphenhydramine 
Disulfiram 
Doxycycline 
Efavirenz 
Enoxacin 
Entacapone 
Ergotamine 
Erythromycin 
Ethinyl estradiol 
Fluconazole 
Fluoroquinolones 
Fluoxetine 
Fluvastatin 
Fluvoxamine 
Fosamprenavir 
Furafilline  
Gestodene 
Grapefruit juice (2) 
Haloperidol 
Hydralazine 
Hydroxyzine 
Interferon 
Itraconazole 
Imatinib 
Indinavir 
Isoniazid 
Itraconazole 
Ketoconazole 
Lomustine 
Methadone 
Methimazole 
Methoxsalen 
Metoclopramide 
Metronidazole 
Mibefradil 
Miconazole 
Mifepristone 
Modafinil 
Nefazodone 
Nelfinavir 
Nevirapine 
Nicardipine 
Nifedipine 
Nizatidine 
Norfloxacin 
Omeprazole 
Orphenadrine 
Paroxetine 
 
Perphenazine 
Phencyclidine 
Pilocarpine 
 
Primaquine 
Propoxyphene 
Quinidine 
Quinine 
Quinupristin 
Ranitidine 
Ranolazine 
Ritonavir 
Saquinavir 
Sertraline 
 
Star fruit 
Sulconazole 
Telithromycin 
Tetracycline 
Thiotepa 
Ticlopidine 
Topiramate 
Tranylcypromine 
Trimetropin 
Troleandomycin 
Valproic acid 
Venlafaxine 
Verapamil 
Voriconazole 
Zafirlukast 
 
CYP3A4 Inducers 
Aminoglutethimide 
Barbiturates 
β-naphthoflavone 
Carbamazepine 
Dexamethasone 
Efavirenz 
Ethanol 
Fosphenytoin 
Glucocorticoids 
 
Modafinil 
Nafcillin  
Nevirapine 
Oxcarbazepine 
Pentobarbital 
Phenobarbital  
Phenytoin 
Primidone 
Rifabutin 
Rifampin  
Rifapentine 
Secobarbital 
St. John’s wort (3) 
Troglitazone 
 
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. 
 
Rev. 2/13 
Rev. 2/13 

ECOG-ACRIN 
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Version Date: July 31, 2014 
 
NCI Update Date: July 2, 2013 
89 
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. 
 

ECOG-ACRIN 
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Version Date: July 31, 2014 
 
NCI Update Date: July 2, 2013 
90 
Androgen Receptor Modulation 
Phase II, Randomized Study of MK-2206 - Bicalutamide Combination in Patients With 
Rising PSA at High-Risk of Progression After Primary Therapy 
 
Appendix VII 
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 
 

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Levofloxacin 
6-8 hours 
48 
 
Levomethadyl 
Multiple compartment PK with active metabolite 
2.6 day for LAAM, 2 day for nor-LAAM, 4 day for 
dinor-LAAM 
 
20 
Lithium 
24 hour (10-50) 
 
7 
 
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 

ECOG-ACRIN 
E2809 
Cancer Research Group 
Version Date: July 31, 2014 
 
NCI Update Date: July 2, 2013 
92 
Androgen Receptor Modulation 
Phase II, Randomized Study of MK-2206 - Bicalutamide Combination in Patients With 
Rising PSA at High-Risk of Progression After Primary Therapy 
 
Appendix VIII 
 
Performance Status Criteria 
 
ECOG Performance Status Scale 
 
 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity. Fully active, able to 
carry on all pre-disease performance 
without restriction. 
100 
Normal, no complaints, no evidence of 
disease. 
90 
Able to carry on normal activity; minor 
signs or symptoms of disease. 
1 
Symptoms, but ambulatory. 
Restricted in physically strenuous 
activity, but ambulatory and able to 
carry out work of a light or sedentary 
nature (e.g., light housework, office 
work). 
80 
Normal activity with effort; some signs 
or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed < 50% of the time. Ambulatory 
and capable of all self-care, but 
unable to carry out any work 
activities. Up and about more than 
50% of waking hours. 
60 
Requires occasional assistance, but is 
able to care for most of his/her needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed > 50% of the time. Capable of 
only limited self-care, confined to bed 
or chair more than 50% of waking 
hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated. Death not imminent. 
4 
100% bedridden. Completely 
disabled. Cannot carry on any self-
care. Totally confined to bed or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes progressing 
rapidly. 
5 
Dead. 
0 
Dead.