Clinical trial NCT02091531
Conditions: Metastatic Castration-Resistant Prostate Cancer
Keywords: mTOR Inhibitor MLN0128 PSA 13-143
Sponsor: Memorial Sloan Kettering Cancer Center
Start date: 2014-03-01; Completion date: 2018-10-01
Enrollment: 9 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a phase II study which will test the study drug MLN0128 in patients with castration resistant prostate cancer who have received chemotherapy in the past. Phase II clinical trials test how well an investigational drug works in treating a specific cancer. "Investigational" means that the drug is still being studied and that research doctors are trying to find out more about it. MLN0128 is not approved by the FDA.

The purpose of this study is to see what effects (good and bad) the study drug MLN0128 has on the patient and the cancer. MLN0128 is a drug that belongs to a class of drugs called "mTOR kinase inhibitors". A protein, called "mTOR" inside the cells in the body, plays a role in controlling how cells grow. In some cancer cells, mTOR may be over-active. This over-activity may cause some cancer cells to grow out of control. Research has shown that mTOR inhibitors can block this overactivity and may help stop or slow down the growth of some types of cancer cells.

Detailed description:

Arms: arm 1: Patients will be treated with the established phase II dose of MLN0128 (4mg po daily continuously; 1 cycle=4 weeks) to assess mechanisms of sensitivity and resistance in men with CRPC who have received either enzalutamide and/or abiraterone.
Interventions: intervention 1: MLN0128
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_SAP_000.pdf: 
MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 13-143 A(6)
Amended:  21-OCT-2015
Page  1 of 77 
Ver. Date: 08/19/11
 
 
 
A Phase 2 Study of the Dual mTOR Inhibitor MLN0128 in 
Patients with Metastatic Castration-Resistant Prostate Cancer (CRPC) 
 
PROTOCOL FACE PAGE FOR 
MSKCC THERAPEUTIC/DIAGNOSTIC PROTOCOL 
 
 
Principal Investigator/Department: 
Dana Rathkopf, MD 
Medicine/Genitourinary 
Co-Principal 
Investigator(s)/Department: 
Howard Scher, MD 
Medicine/Genitourinary 
Investigator(s)/Department: 
Michael Morris, MD 
Yu Chen, MD, PhD 
Susan Slovin, MD, PhD 
David Solit, MD 
Daniel Danila, MD 
Lewis J. Kampel, MD 
Karen Autio, MD 
Jason Koutcher, MD, PhD 
James Hsieh, MD, PhD 
Martin Voss, MD 
Gopakumar Iyer, MD 
Jonathan Rosenberg, MD 
Anthony DeLaCruz, RN, NP 
Tracy B. Curley, RN 
Gabrielle Arauz, RN 
Richard Bambury, MB, BCh, BAO 
Josef Fox, MD 
Jonathan Landa, DO 
Steve Larson, MD 
Jeremy Durack, MD 
Joseph Osborne, MD, PhD 
Glenn Heller, PhD 
Victor Reuter, MD 
Martin Fleisher, PhD 
Medicine/Genitourinary 
Radiology/Nuclear Medicine 
Radiology 
Epidemiology and Biostatistics 
Pathology 
Laboratory Medicine 
Consenting 
Professional(s)/Department: 
Dana Rathkopf, MD 
Howard Scher, MD 
Yu Chen, MD, PhD 
Michael Morris, MD 
Medicine/Genitourinary 


MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 13-143 A(6)
Amended:  21-OCT-2015
Page  2 of 77 
Ver. Date: 08/19/11
 
 
Susan Slovin, MD, PhD 
David Solit, MD 
Daniel Danila, MD 
Lewis J. Kampel, MD 
Karen Autio, MD 
Jason Koutcher, MD, PhD 
James Hsieh, MD, PhD 
Martin Voss, MD 
Gopakumar Iyer, MD 
Jonathan Rosenberg, MD 
Richard Bambury, MB, BCh, BAO 
 
 
 
Please Note: A Consenting Professional must have completed the mandatory Human 
Subjects Education and Certification Program. 


MEMORIAL SLOAN-KETTERING CANCER CENTER 
IRB PROTOCOL 
IRB#: 13-143 A(6)
Amended:  21-OCT-2015
Page  3 of 77 
Ver. Date: 08/19/11
 
 
Memorial Sloan-Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Table of Contents 
 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA .................................................................... 7 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS .............................................................................. 9 
 
3.0 
BACKGROUND AND RATIONALE .................................................................................10 
3.1 
Disease Background ..........................................................................................................10 
3.2 
MLN0128 ..........................................................................................................................11 
3.2.1 
Preclinical Studies ...............................................................................................................11 
3.2.2 
Clinical Studies ....................................................................................................................14 
3.2.3 
Potential Risks and Benefits ................................................................................................16 
3.3 
Correlative Studies ............................................................................................................17 
3.3.1 
Tumor biopsies ....................................................................................................................17 
3.3.2 
CTC enumeration and molecular profiling ..........................................................................17 
3.3.3 
FDG and FDHT PET imaging.................................................................................................18 
3.4 
Rationale for conducting the study ....................................................................................18 
 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION ...........................................................19 
4.1 
Design ..............................................................................................................................19 
4.2 
Intervention......................................................................................................................19 
4.2.1 
Treatment Administration ..................................................................................................19 
4.2.2 
Dosing Schedule ..................................................................................................................20 
4.2.3 
Treatment Compliance........................................................................................................20 
4.2.4 
Re-treatment Criteria ..........................................................................................................20 
4.2.5 
Dose Modifications .............................................................................................................20 
4.3 
Management of Clinical Events ..........................................................................................21 
4.3.1 
Management of Hyperglycemia..........................................................................................21 
4.3.2 
Management of Noninfectious Pneumonitis ......................................................................22 
4.3.3 
Management of Hyperlipidemia .........................................................................................23 
4.3.4 
Management of Oral Mucositis ..........................................................................................24 
4.3.5 
Management of Rash ..........................................................................................................25 
4.3.6 
Management of Nausea and/or Vomiting ..........................................................................25 
4.3.7 
Management of Cardiac Events ..........................................................................................26 
4.3.8 
Management of Other Toxicities ........................................................................................27 
4.4 
Concomitant Medications .................................................................................................29 
4.4.1 
Supportive care medications ..............................................................................................29 
4.4.2 
Prohibited therapies............................................................................................................30 
4.4.3 
Restricted therapies ............................................................................................................30 
4.4.4 
Washout periods for prohibited medications.....................................................................30 


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5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS ..........................................................................31 
5.1 
Pharmacology ...................................................................................................................31 
5.2 
Packaging and Labeling .....................................................................................................31 
5.3 
Storage and Accountability................................................................................................31 
5.3.1 
Storage requirements .........................................................................................................31 
5.3.2 
Drug dispensing log and pill diary .......................................................................................31 
 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY .............................................................................32 
6.1 
Subject Inclusion Criteria ...................................................................................................32 
6.2 
Subject Exclusion Criteria ..................................................................................................33 
 
7.0 
RECRUITMENT PLAN ..................................................................................................35 
 
8.0 
PRETREATMENT EVALUATION....................................................................................35 
8.1 
Screening (Day -30 to Day 1) ..............................................................................................35 
8.2 
Baseline Evaluation (Day -14 to Day 1) ...............................................................................35 
 
9.0 
TREATMENT/INTERVENTION PLAN.............................................................................36 
9.1 
Cycle 1, Week 1 (Day 1) .....................................................................................................36 
9.2 
Cycle 1, Week 2 (Day 8±1 day) ...........................................................................................36 
9.3 
Cycle 1, Week 3 (Day 15±1 day) .........................................................................................36 
9.4 
Cycle 1, Week 4 (Day 22±1 day) .........................................................................................36 
9.5 
Cycle 2, Week 1 (Day 1±2 day) ...........................................................................................37 
9.6 
Cycle 2, Week 2 (Day 8±2 day) ...........................................................................................37 
9.7 
Cycle 2, Week 3 (Day 15±2 day) .........................................................................................37 
9.8 
Cycle 2, Week 4 (Day 22±2 day) .........................................................................................37 
9.9 
Cycle 3, Week 1 (Day 1±2 day) ...........................................................................................38 
9.10 
Cycle 3, Week 3 (Day 15±2 day) .........................................................................................38 
9.11 
Cycle 4, Week 1 (Day 1±2 day) ...........................................................................................38 
9.12 
Cycle 4, Week 3 (Day 15±2 day) .........................................................................................38 
9.13 
Cycle 5 through end of treatment ......................................................................................39 
9.14 
Every 8 weeks (± 7 days)....................................................................................................39 
9.15 
End-of-treatment visit .......................................................................................................39 
9.16 
Follow-up (30 days or until death) .....................................................................................39 
 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION ...................................................39 
10.1 
Medical History .................................................................................................................40 
10.2 
Physical Examination.........................................................................................................40 
10.3 
Performance Status...........................................................................................................40 
10.4 
Cardiac Function ...............................................................................................................40 
10.5 
Clinical Laboratory Tests....................................................................................................41 
10.5.1 
Laboratory parameters .......................................................................................................41 
10.5.2 
Sample collection, storage and shipping.............................................................................41 
10.6 
Efficacy Assessments .........................................................................................................41 
10.7 
Tumor Biopsies .................................................................................................................42 


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10.8 
Circulating Tumor Cell Studies ...........................................................................................42 
10.9 
Whole Blood Lymphocyte Assay ........................................................................................43 
10.10   Buffy Coat for Germline DNA.............................................................................................43 
10.11   FDG and FDHT PET ............................................................................................................43 
 
11.0 
TOXICITIES/SIDE EFFECTS ...........................................................................................43 
11.1 
Defining Adverse Events ....................................................................................................43 
11.1.1 
Adverse Event (AE) ..............................................................................................................43 
11.1.2 
Unexpected Adverse Event .................................................................................................45 
11.1.3 
Adverse Events of Special Interest ......................................................................................45 
11.1.4 
Serious Adverse Event (SAE) ...............................................................................................45 
11.2 
Recording Adverse Events .................................................................................................46 
11.2.1 
Timeframe for Recording Adverse Events and Serious Adverse Events .............................46 
11.2.2 
Recording of Adverse Events and Serious Adverse Events .................................................46 
11.3 
Grading Adverse Events.....................................................................................................47 
11.3.1 
Grading severity ..................................................................................................................47 
11.3.2 
Attributing causality ............................................................................................................47 
 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT...............................47 
 
13.0 
CRITERIA FOR REMOVAL FROM STUDY.......................................................................48 
13.1 
Definition of Progression ...................................................................................................48 
13.2 
Safety Evaluation ..............................................................................................................49 
 
14.0 
BIOSTATISTICS ...........................................................................................................49 
14.1 
Analysis Population...........................................................................................................49 
14.2 
Demographics and Baseline Characteristics........................................................................49 
14.3 
Safety Analysis ..................................................................................................................49 
14.3.1 
Adverse events ....................................................................................................................49 
14.3.2 
Clinical laboratory tests.......................................................................................................49 
14.4 
Statistical Procedures ........................................................................................................49 
 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES...........50 
15.1 
Research Participant Registration ......................................................................................50 
15.2 
Randomization..................................................................................................................51 
 
16.0 
DATA MANAGEMENT.................................................................................................51 
16.1 
Quality Assurance .............................................................................................................51 
16.2 
Data and Safety Monitoring...............................................................................................51 
16.2.1 
Data Collection and Review ................................................................................................51 
16.2.2 
Source documents...............................................................................................................52 
16.2.3 
Record retention .................................................................................................................52 
 
17.0 
PROTECTION OF HUMAN SUBJECTS............................................................................52 
17.1 
Privacy ..............................................................................................................................52 
17.2 
Serious Adverse Event (SAE) Reporting ..............................................................................52 


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17.2.1 
Millennium Reporting timelines .........................................................................................52 
17.2.2 
Millennium Procedures for Reporting Serious Adverse Events ..........................................52 
17.2.3 
Millennium Procedures for Reporting Drug Exposure During Pregnancy ..........................54 
17.2.4 
MSKCC Procedures for Reporting Serious Adverse Events .................................................56 
17.2.5 
Adverse events ....................................................................................................................57 
17.2.6 
Clinical laboratory tests.......................................................................................................57 
 
18.0 
INFORMED CONSENT PROCEDURES............................................................................57 
 
19.0 
REFERENCES...............................................................................................................59 
 
20.0 
APPENDICES...............................................................................................................61 
Appendix A: Performance Status Criteria ......................................................................................61 
Appendix B: Study Calendar .........................................................................................................62 
Appendix C: Circulating Tumor Cell (CTC) Laboratory Manual ........................................................64 
Appendix D: Glossary of Abbreviations and Acronyms ..................................................................68 
Appendix E: Pill Diary ...................................................................................................................72 
Appendix F: Glucose Monitoring Diary ..........................................................................................74 
Appendix G: New York Heart Association Classification of Cardiac Disease ....................................76 
Appendix H: Strong Inhibitors and Inducers of CYP2C9, CPY2C19, and CYP3A4 ...............................77 


IRB#: 13-143A(6) 
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1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
 
 
 
 
Title 
A Phase 2 Study of the Dual mTOR Inhibitor MLN0128 in Patients with 
Metastatic Castration-Resistant Prostate Cancer (CRPC) 
Investigational agent MLN0128, an orally-available, potent and selective TORC1/2 inhibitor 
Target population 
Men with metastatic CRPC who have  no prior exposure to PI3K/mTOR 
pathway inhibitors. 
Expected enrollment 21-42 
Rationale 
Dysregulated activation of the PI3K signaling pathway is one of the most 
common alterations in human prostate cancer—both at initial diagnosis and 
at the time of relapse to castration-resistant disease. Loss of the tumor 
suppressor PTEN is by far, the most common mechanism of PI3K pathway 
activation, with PTEN gene copy number loss present in 42% of primary 
tumors and 100% of metastatic castrate-resistant prostate cancers.1 
Despite the high rate of PI3K pathway dysregulation in CRPC, inhibition of 
the downstream regulator TORC1 using rapalogs has been disappointing in 
the clinic.2-4 With further elucidation of the PI3K signaling pathway, we now 
realize that the lack of response to treatment with these rapalogs is likely 
due to the demonstrable role of TORC2 (not inhibited by rapalogs) in 
models of PTEN-driven prostate cancer,5 and also to negative feedback 
inhibition on AR and other oncogenic pathways that maintain cell survival.6-8 
 
MLN0128 is a first in class, dual mTOR inhibitor that has the potential to 
overcome resistance seen with standard rapalogs through inhibition of both 
TORC 1 and 2, and inhibitory effects on cancer cell invasion and metastasis 
through regulation of 4EBP1-eIF4E . We will evaluate MLN0128 in this 
single agent phase II study for patients with CRPC with the goal of 
determining anti-tumor activity and dissecting mechanisms of sensitivity and 
resistance to this agent using correlative studies such as circulating tumor 
cells, FDG and FDHT PET imaging, and tumor biopsies when possible. 


IRB#: 13-143A(6) 
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Objectives 
Primary: To evaluate the antitumor effects of MLN0128 by determining 
progression-free survival (PFS) at 6 months. 
 
Secondary Endpoints: PSA kinetics, Radiographic Response 
 
Exploratory Endpoints: 
• 
To explore baseline and changes in biomarker expression (eg, PTEN, 
AR, TMPRSS2-ERG , pS6K, p4EBP1, pAKT, AR, PHLPP 1 and 2 )  in 
pre- and post-therapy tumor biopsies. 
• 
To explore pre- and post-therapy changes in circulating tumor cell (CTC) 
number and biomarker expression (ie: PTEN, AR). 
• 
To study the accumulation and biodistribution of fluoro-2-deoxy-D- 
glucose (FDG) and fluorinated dihydrotestosterone (FDHT) in patients 
treated with MLN0128. 
 
Study design 
Patients will be treated with the established phase II dose of MLN0128 (4 
mg po daily continuously; 1 cycle=4 weeks) to assess mechanisms of 
sensitivity and resistance in men with CRPC who have received either 
enzalutamide and/or abiraterone. 
 
Criteria for 
evaluation 
Primary Endpoint: Progression-free survival (PFS) at 6 months from the 
start of treatment, as defined by the Prostate Cancer Working Group 2 
(PCWG2) guidelines. 
 
Secondary Endpoints: PSA kinetics, Radiographic Response 
 
Exploratory Endpoints: Pre and post-treatment tumor biopsies for IHC, 
circulating tumor cell enumeration and molecular analysis, FDG and 
FDHT PET imaging. 


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Statistical method 
The primary objective of this study is to determine the efficacy of MLN0128 
in patients with metastatic castration- resistant prostate cancer. The primary 
endpoint of the study is six month progression free survival (6mPFS). A 
patient that is followed for six months and remains progression free during 
this time period is defined as a success. 
 
Recently there have been two phase III studies demonstrating an overall 
survival benefit for patients with CRPC. The 6mPFS endpoint has therefore 
been selected based on these single agent studies using the hormonal 
intervention abiraterone (6mPFS 44%) and chemotherapy cabazitaxel 
(6mPFS 23%). In this study, a two-stage design that differentiates between 
6mPFS rates of 0.30 and 0.50 will be used to assess treatment efficacy. In 
the first stage of the study 21 patients will be enrolled. If at most 6 patients 
remain alive and progression free at 6 months, accrual will be terminated. If 
at least 7 patients are alive and progression free at 6 months, an additional 
21 patients will be accrued in this cohort. At the conclusion of this second 
stage, if at least 17/42 patients remain alive and progression free at 6 
months, then the treatment will be declared sufficiently active. The 
probability of declaring the treatment effective is 0.10 when the 6mPFS in 
the population is 0.30 and increases to 0.90 when the 6mPFS is 0.50. It is 
anticipated that accrual in this trial will be completed in approximately 1-2 
years. 
 
Circulating tumor cells, FDG PET imaging, and FDHT PET imaging will be 
recorded over time and their temporal association with progression-free 
survival time (and overall survival time) will be modeled using a time- 
dependent Cox model. 
 
Safety analysis 
Standard safety summaries will be provided for treatment exposure, patient 
disposition, adverse events leading to discontinuation, serious adverse 
events, and all events resulting in death, including those up to 30 days after 
treatment discontinuation. The incidence of adverse events will be tabulated 
and reviewed for potential significance and clinical importance. 
 
 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
Primary Objective 
To evaluate the antitumor effects of MLN0128 by determining progression-free survival 
(PFS) at 6 months. 
 
Secondary Objectives 
 
PSA kinetics and radiographic response 


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Exploratory Endpoints 
To explore changes in biomarker expression in pre- and post-therapy tumor biopsies. 
To explore pre- and post-therapy changes in circulating tumor cell (CTC) number and 
biomarker expression. 
 
To study the accumulation and biodistribution of fluoro-2-deoxy-D-glucose (FDG) and 
fluorinated dihydrotestosterone (FDHT) in patients treated with MLN0128. 
 
3.0 
BACKGROUND AND RATIONALE 
 
3.1 
Disease Background 
Prostate cancer is the second leading cause of cancer deaths in men. It is estimated 
that there are 142,000 men in the US in this state who require active treatment (Figure 
1).9 
 
The course of prostate cancer from diagnosis to death is best categorized as a series of 
clinical states (Figure 1).10 These clinical states involve the complex interplay of a 
network of signaling molecules that collectively promote net cell proliferation relative to 
cell death. Based on the extent of disease, hormonal status, and absence or presence of 
detectable metastases on an imaging study, the states are localized disease, rising 
levels of prostate-specific antigen (PSA) after radiation therapy or surgery with no 
detectable metastases, and clinical metastases in the non-castrate or castrate state. 
 
Figure 1. Clinical states of prostate cancer 
 
Clinical 
Metastases: 
Non-Castrate 
 
 
2 
Clinical 
Metastases: 
Castrate 
 
 
3 
Clinical 
Metastases: 
 
 
4 
Clinical 
Metastases: 
Castrate 
Clinically 
Localized 
Disease 
  
 
Neoadjuv ant 
Adjuv ant 
Rising 
PSA 
  
 
 
142,000 
 
1 
Rising PSA: 
Castrate 
 
Trial in Dev elopment 
Pre- 
Provenge 
Abiraterone 
302 
Castrate 
1st Line 
Docetaxel 
Post- 
Cabazitaxel 
Abiraterone 
301 
 
 
Although surgery, radiation, or a combination of both can be curative for patients with 
localized disease, a significant proportion of these patients have recurrent disease as 
evidenced by a rising level of PSA, which, if left untreated, is followed by detectable 
metastases on imaging studies. For these individuals, the issue is to determine whether 
the disease is local or systemic, and if the later, the risk of developing metastatic 
disease – a transition to the lethal phenotype of the illness and in what time frame. 
Androgen depletion is the standard treatment with a generally predictable outcome: an 
initial apoptotic response, a period of quiescence in which tumor does not proliferate, 
followed unfortunately by disease progression. Once the castration-resistant phenotype 
has become manifest, docetaxel, the standard first-line chemotherapy, is not curative, 
and most patients succumb to their disease. Second-line or third-line hormonal therapy 


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can induce post-treatment-PSA declines in 20-30% of patients, but these have never 
been shown to impact overall survival. 
 
 
 
 
3.2 
MLN0128 
 
MLN0128 (formerly INK128) is an orally bioavailable, potent, highly selective, adenosine 
5’ triphosphate (ATP)-competitive inhibitor of the serine/threonine kinase referred to as 
the metabolic target of rapamycin (mTOR). The mTOR is a kinase that regulates cell 
growth, translational control, angiogenesis, and cell survival by integrating nutrient and 
hormonal signals. mTOR kinase plays a key role in several pathways that are frequently 
dysregulated in human cancer.11 The mTOR complex (mTORC) is an important 
therapeutic target that is stable (does not mutate) and is a key intracellular point of 
convergence for a number of cellular signaling pathways. Inhibiting mTOR may inhibit 
abnormal cell proliferation, tumor angiogenesis, and abnormal cellular metabolism, thus 
providing the rationale for mTOR inhibitors as potential agents as either monotherapy or 
in combination with other chemotherapeutic agents in the treatment of solid tumor and 
hematological malignancies. 
 
The mTOR kinase operates in 2 distinct multi-protein complexes, mTORC1 and 
mTORC2. mTORC1 is best known as a key regulator of protein translation through 
phosphorylation of 4EBP1, the eukaryotic translation initiation factor, and S6 kinase. 
mTORC2 is best known for its ability to fully activate AKT by phosphorylation on the 
S473 site, which regulates proliferation and survival pathways.12 Analogs of the natural 
product rapamycin (known as rapalogs) have demonstrated therapeutic benefit in 
several cancer types, including renal, non-small cell lung cancer (NSCLC), 
neuroendocrine and hematologic malignancies. 13,14 
 
However, rapalogs can be considered partial inhibitors of mTORC1. Additionally, 
inhibition of only mTORC1 without mTORC2 leads to reactivation (by inhibition of 
feedback regulation) of AKT, which is involved in cancer cell survival, proliferation, 
growth, metabolism, angiogenesis, and metastasis. 15 Inhibition of AKT activity through 
mTORC2 inhibition has been shown to prevent the AKT activation induced by mTORC1 
inhibition. 
 
To address the incomplete inhibition of mTOR by rapalogs, MLN0128 was developed. 
MLN0128 is a potent, selective, orally bioavailable, ATP-competitive inhibitor of mTOR 
that is currently in phase 1 clinical trials. MLN0128 targets both mTORC1 and mTORC2, 
and is designed to overcome the shortcomings of the current rapalogs to achieve 
greater clinical benefit. 
 
3.2.1 Preclinical Studies 
 
Nonclinical studies have been conducted to demonstrate the mechanism of action, 
efficacy, and safety of MLN0128 in biological models to characterize 
pharmacodynamics, define the pharmacokinetic (PK) properties, characterize the toxicity 
profile, and support a safe starting dose in humans for MLN0128 drug product. 


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Pharmacology 
 
MLN0128 selectively and potently inhibits mTOR kinase (IC50 = 1.1 nM), inhibits 
mTORC1/2 signaling, and prevents cellular proliferation. The in vitro cellular potency of 
MLN0128 was not diminished in the presence of human whole blood components. 
 
The pharmacodynamics and antitumor activity of MLN0128 was studied in vivo in murine 
xenograft models of human glioblastoma, NSCLC, breast cancer, renal cell cancer, 
endometrial adenocarcinoma, and castration-resistant prostate cancer (CPRC). 
Consistent with the mode of action, MLN0128 inhibited phosphorylation of downstream 
modulators of mTORC1 (namely 4EBP1 and S6) and mTORC2 (namely AKT [S473]) in 
human U87 glioblastoma tumor xenograft models in mice at doses as low as 0.1 mg/kg. 
Additionally, 
 
MLN0128 showed strong tumor growth inhibition (TGI) in all 8 xenograft models at 
tolerable oral (PO) doses from 0.15 mg/kg (daily [QD]; tested in MDA-MB-361 breast 
carcinoma) to 3.0 mg/kg (every other day [Q2D] or once weekly [QW]; tested in all 
models). 
 
In addition to single-agent activity in these xenograft models, MLN0128 was combined 
with the standard of care (SOC) agent paclitaxel in the breast and endometrial models. 
The combination of MLN0128 with paclitaxel resulted in enhanced antitumor activity and 
reduced tumor burden. When tumors were pretreated with paclitaxel, there was an 
added benefit in tumor reduction compared to the effects of simultaneous administration 
of both agents, consistent with the mechanism of action of paclitaxel. Findings from 
these nonclinical pharmacology studies suggest that MLN0128, alone and in 
combination with paclitaxel, has therapeutic potential as an orally administered 
mTORC1/2 inhibitor for the treatment of cancers associated with dysregulated activation 
of the PI3K/AKT/mTOR pathway, such as renal cell, endometrial, breast, lung, and 
prostate cancers. 
 
Drug Metabolism and Pharmacokinetics 
 
MLN0128 was rapidly absorbed after oral administration to mice, rats, dogs, and 
monkeys, with high oral bioavailability. MLN0128 did not inhibit P-glycoprotein (P-gp). 
 
A study of the tissue distribution of [14C]MLN0128 showed that [14C]MLN0128 was 
rapidly and widely distributed throughout the body in Long-Evans rats; radioactivity was 
eliminated from most tissues at 48 hours postdose, and from all but the adrenal cortex, 
adrenal gland, adrenal medulla, eye, liver, and uveal tract at 168 hours. MLN0128 
displayed doseproportional plasma exposures and a moderate propensity to cross the 
blood-brain barrier. MLN0128 was modestly bound to human plasma proteins 
(approximately 70%). MLN0128 inhibited breast cancer resistance protein (BCRP), 
organic cation transporter (OCT)1, and OCT2. 


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M1, the single metabolite (monohydroxylation product) observed in human microsomal 
incubations, was also observed in rats and monkeys, the species used for the Good 
Laboratory Practice (GLP) toxicology studies. The main isozymes responsible for phase 
1 metabolism appear to be cytochrome P450 (CYP) 2C9, 2C19, and 3A4. MLN0128 
displayed low potential (IC50 > 30 µM) for inhibition of CYP1A2, 2C19, 2C8, 2C9, 
CYP2D6, and 3A4. MLN0128 did not induce CYP1A2, 2B6, and 3A4 activity and 
expression at concentrations up to 30 µM. 
 
Oral administration of MLN0128 in humans has a low potential for metabolic and 
transporter-based drug-drug interactions (DDIs), especially given clinical exposures 
observed to date after administration of the highest single dose (total maximum plasma 
concentration [Cmax] of 0.64 µM [free Cmax of 0.19 µM] at 40 mg QW). 
 
Toxicology 
 
The MLN0128 toxicology program consisted of single- and repeat-dose studies in rats 
and monkeys, single-dose studies in dogs, and an Ames genotoxicity study. 
 
The toxicologic profiles obtained in the non-GLP-compliant and GLP-compliant studies 
were generally consistent. The observed toxicities were consistent between rats and 
monkeys, with no apparent sex differences. 
 
The toxicity profile of MLN0128 in rats and monkeys, as established in GLP-compliant 
repeat-dose studies, is consistent with pharmacologic inhibition of mTORC1/2 activity. 
The dose limiting toxicities (DLTs) of MLN0128 in rats and monkeys were secondary to 
an exaggerated pharmacologic response and consisted of body weight loss and 
associated clinical observations that included gastrointestinal (GI) distress and 
decreased activity, appetite, and body temperature. Adverse effects in rats included 
body weight loss, decreased activity, increased glucose and insulin levels, alterations in 
white blood cells (WBCs), bone marrow and lymphoid depletion, thymic necrosis, 
oligospermia, testes degeneration/atrophy, nonglandular stomach epithelial 
degeneration/ulceration/hyperplasia, and alveolar histiocytosis. The microscopic findings 
observed in the testes, epididymides, and nonglandular stomach were not resolved after 
a 14-day recovery period, while partial to complete resolution was seen in the lungs, 
thymus, and bone marrow. The adverse effects in monkeys included decreased activity, 
appetite, and body weight; increased glucose and insulin; lymphoid and bone marrow 
depletion; adrenal hypertrophy/hyperplasia; pancreatic and salivary gland acinar cell 
secretory depletion; GI tract erosion and ulceration; and skin ulceration/epidermal 
hyperplasia. The findings in the pancreas, adrenal glands, and salivary glands may have 
been related to a stress response or reduced food consumption. The findings were 
generally reversible after a 14-day recovery period. 
 
The findings in rat and monkey repeat-dose toxicology studies with MLN0128, including 
bone marrow and lymphoid depletion, GI and skin effects, and effects on glucose and 
insulin levels, can be monitored in clinical trials. The toxicities seen in the repeat-dose 
toxicology studies, such as GI effects and glucose and insulin increases, are consistent 
with the treatment-emergent adverse events (TEAEs), including mucositis and 
hyperglycemia, observed to date in patients receiving MLN0128. 


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MLN0128 was negative for mutagenicity in the Ames assay, and shows low potential for 
phototoxicity. 
 
3.2.2 Clinical Studies 
 
Single-agent MLN0128 is in clinical development in two phase 1 studies in subjects with 
advanced solid malignancies and hematologic malignancies (multiple myeloma [MM] 
and Waldenstrom macroglobulinemia [WM]), and in a third study in combination with 
paclitaxel with or without trastuzumab in subjects with advanced solid tumors. 
 
Study INK128-001 
 
Study INK128-001 is evaluating safety and anti-tumor activity of MLN0128 in subjects 
with advanced solid malignancies. As of 09 December 2012, 106 subjects have been 
treated in Study INK128-001. The most common adverse events (AEs) (≥ 20%), 
regardless of causality were hyperglycemia (64%), nausea (60%), vomiting (49%), 
decreased appetite (40%), diarrhea (37%), asthenia (35%), fatigue and mucosal 
inflammation (28% each), rash (27%), and pruritus (24%). Most commonly reported (> 
3%) Grade ≥ 3 AEs, regardless of causality, include hyperglycemia (10%), asthenia 
(7%), anemia (6%), lymphopenia (6%), hypophosphatemia (5%), mucosal inflammation 
(5%), and rash (5%). 
 
In Study INK128-001, as of 09 December 2012, the maximum tolerated doses (MTD) for 
all 4 schedules has been determined: for the QD dosing the MTD is 6 mg QD, for the 
QDx3dQW dosing, the MTD is 16 mg; for the QDx5dQW dosing, the MTD is 10 mg; and 
for the QW dosing schedule, the MTD is 40 mg. The MTDs for each of the 4 schedules 
was determined by evaluation of cohorts of 6 evaluable patients. At each MTD, up to 6 
additional patients were enrolled to further evaluate safety and tolerability. A significant 
proportion of patients treated at the MTDs required dose modifications due to drug- 
related AEs beyond 1 or 2 cycles, and therefore were not representative of a 
recommended phase 2 dose. The study is currently further evaluating doses at less than 
the MTD for QDx3dQW and QDx5dQW, to determine a dose(s) and schedule(s) to be 
studied further in the expansion phase of the study, as well as in future phase 2 studies. 
The dose escalation portion of the study has evaluated dose regimens ranging from 2 to 
7 mg QD, 7 to 40 mg QW, 6 to 20 mg QDx3dQW, and 7 to 13 mg QDx5dQW. 
 
Study INK128-002 
 
Study INK128-002 is evaluating safety and anti-tumor activity of MLN0128 in subjects 
with hematologic malignancies (MM and WM). As of 09 December 2012, 39 subjects 
have been treated in Study INK128-002. The most common AEs (≥ 20%), regardless of 
causality were fatigue and nausea (51% each), hyperglycemia (38%), thrombocytopenia 
(36%), diarrhea (26%), decreased appetite and vomiting (23% each), and 
stomatitis/anemia (21% each). 
 
Most commonly reported (at least 2 subjects) Grade ≥ 3 AEs, regardless of causality 
included thrombocytopenia (18%), fatigue (10%), neutropenia (8%), hypocalcemia (5%), 
hypophosphatemia (5%), mucosal inflammation (5%), and pneumonia (5%). 


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In Study INK128-002, dose escalation is completed, with 4 mg determined as the MTD 
for the QD schedule, and 9 mg determined as the MTD for the QDx3dQW schedule. 
 
 
 
Study INK128-003 
 
Study INK128-003 is evaluating safety and anti-tumor activity of MLN0128 in subjects 
with advanced solid tumors in combination with paclitaxel (and trastuzumab for HER2+ 
subjects). As of 09 December 2012, 48 subjects have been treated in Study INK128- 
003; no subject has been treated with trastuzumab. The most common AEs (≥ 20%), 
regardless of causality were fatigue (67%); nausea (56%); diarrhea (50%); dehydration 
and hyperglycemia (44% each); anemia (40%); anorexia, mucosal inflammation, and 
vomiting (38% each); rash (35%); asthenia and neutropenia (31% each); hypokalemia 
(27%); hypophosphatemia and urinary tract infection (23% each); and constipation 
(21%). Most commonly reported (at least 2 subjects) Grade ≥ 3 AEs, regardless of 
causality, include neutropenia (23%); hypophosphatemia (17%); diarrhea, fatigue, and 
hyperglycemia (15%); and dehydration (10%). 
 
In the dose expansion phase of this study, additional subjects were enrolled once the 
MTD was determined and evaluated for each of the dosing schedules. These subjects 
were enrolled into an arm of HER2- subjects receiving MLN0128 in combination with 
paclitaxel (n = 11) at the MTD or an arm of HER2+ subjects receiving MLN0128 in 
combination with paclitaxel plus weekly trastuzumab (n = 2) at the MTD. The most 
common AEs (≥ 20%), regardless of causality, were alopecia, fatigue, and nausea (23% 
each) and anorexia, asthenia, diarrhea, dyspepsia, mucosal inflammation, neutropenia, 
and vomiting (15% each). Most commonly reported (at least 2 subjects) Grade ≥ 3 AEs 
in the dose expansion phase of INK128-003, regardless of causality, include mucosal 
inflammation, neutropenia, and pneumonia (reported by 1 subject each in the HER2- 
arm). 
 
In Study INK128-003, dose escalation is completed, with 8 mg of MLN0128 QDx3dQW 
being selected for the dose expansion phase of the study. The QDx5dQW and QW 
schedules were abandoned before MTDs were declared, as these schedules were 
viewed as less convenient relative to the QDx3dQW schedule, from the perspective of 
administering the paclitaxel and trastuzumab combination. The dose expansion portion 
of this study is ongoing, with HER2-/unknown patients receiving 8 mg of MLN0128 
QDx3dQW in combination with paclitaxel, and HER2+ patients receiving 8 mg of 
MLN0128 QDx3dQW in combination with paclitaxel and trastuzumab. 
 
PK Summary 
 
Preliminary pharmacokinetic (PK) data from these studies indicate that MLN0128 
exhibits fast oral absorption (first time to maximum plasma concentration [Tmax] 
generally between 1 to 4 hours after dosing) and dose-linear pharmacokinetics with a 
mean plasma half-life of ~8 hours and does not accumulate meaningfully in plasma on 
either dosing regimen. The pharmacokinetics of MLN0128 was generally consistent with 


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no appreciable differences across the three phase 1 studies. Neither paclitaxel nor 
MLN0128 appeared to alter the PK of the other agent when co-administered. 
 
3.2.3 Potential Risks and Benefits 
 
Currently, 206 subjects have participated in phase 1 studies including 145 subjects in 
single agent studies INK128-001 and INK128-002 (N = 106 and N = 39, respectively); 
and 61 subjects in the paclitaxel combination study INK128-003. Toxicities have been 
mostly Grades 1 and 2, reversible, and manageable with supportive care and/or 
interruption or dose reduction of study drug. Commonly reported study drug-related AEs 
have included hyperglycemia, asthenia, fatigue, mucosal inflammation, decreased 
appetite, rash, nausea, vomiting, and diarrhea. This emerging safety profile is consistent 
with those of other TORC1/2 and PI3K pathway inhibitors. 
 
As of 2012, there are no FDA-approved TORC1/2 inhibitors. Rapamycin and rapalogs 
are TORC1 inhibitors with well-described toxicity profiles. Common toxicities include the 
following: immunosuppression with the potential to increase the risk of both nonserious 
and serious infections, and/or malignancies; mucositis, stomatitis, and mouth sores with 
a frequency from 41% to 78%; anorexia (approximately 30%), pneumonitis including 
interstitial lung disease (5%-36%); diarrhea (25%-56%); skin toxicity (48%-66%) which 
manifests typically as maculopapular or acneform rash, skin dryness, eczema, skin 
discoloration, and nail dystrophy; hyperlipidemia (hypercholesteremia and/or 
hypertriglyceridemia) with incidences from 8% to 44%; hyperglycemia (8%-22%); 
thrombocytopenia (10%-33%); anemia (27%-94%); leucopenia (27%-38%); hypokalemia 
(11%-21%); hypophosphatemia (15%-49%); hypertension (4%-7% in renal cancer 
subjects); elevated serum creatinine (37%-57%); elevated liver function tests (about 
20%); arthralgia (25%-30%); asthenia (about 30%); peripheral edema (24%- 
35%)16,17,18,19 Serious infections have included sepsis, opportunistic infections, and even 
death. An increase in the development of lymphomas is also a possibility because of the 
immunosuppression. 
 
Additionally, hypersensitivity reactions (18%), and fatal bowel perforation (1%) have 
been reported. Rapidly progressive, and sometimes fatal, acute renal failure not clearly 
related to renal cancer disease progression, abnormal wound healing, and increased 
risk of developing intracerebral bleeding (including fatal outcomes) in subjects with 
central nervous system (CNS) malignancies and/or receiving anticoagulation therapy 
have been reported in subjects receiving temsirolimus. Because of potential hazard to 
the developing fetus, women of childbearing potential are advised to avoid becoming 
pregnant while receiving Rapamycin or rapalogs.17,18,19 
 
The toxicities of rapamycin or rapalogs are typically reversible and infrequently serious. 
MLN0128 targets both TORC1 and TORC2, and thus may prove to have a different 
risk/benefit profile from the rapalogs. There is no human information available on 
inhibition of TORC2 alone. The safety profile of MLN0128 continues to be explored in 
advanced malignancies, including non-Hodgkin lymphoma (NHL), and hematologic 
malignancies. 


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3.3 
Correlative Studies 
 
3.3.1 Tumor biopsies 
Tissue samples will be utilized for organoid growth, morphologic assessment, percent 
tumor involvement (if applicable), and immunohistochemistry. Samples will be evaluated 
for downstream indicators of PI3K pathway modulation and additional pathways of 
interest. Specific markers may include: pS6K, p4EBP1, pAKT, AR and PHLPP 1 and 2. 
The analysis will be performed under the guidance of Dr. Victor Reuter, and members of 
the MSKCC genitourinary pathology staff will score both staining intensity and the 
percentage of positive cells exhibiting immunoreactivity (as a continuous variable). 
 
3.3.2 CTC enumeration and molecular profiling 
CTC number has been proposed as a marker of prognosis pre-therapy and as a 
surrogate for treatment efficacy post-therapy in phase III clinical trials powered to detect 
a difference in survival with treatment. We have also shown that AR amplification and 
increased AR gene copy number are detected by fluorescence in situ hybridization 
(FISH) in CTCs of more than 50% of patients with progressive CRPC. Currently, we use 
the EpCAM-based immunomagnetic enriched CTC sample to analyze the AR, 
TMPRSS2-ERG and PTEN by FISH, after fixing the cells into the enumeration chambers 
(Neon, Veridex). We propose to explore pre- and post-therapy changes in circulating 
tumor cell (CTC) number as a marker of response efficacy while on treatment on this 
protocol. Genomic alterations in AR, TMPRSS2-ERG and PTEN in CTC isolated at 
baseline will be prospectively tested as a predictive value of treatment sensitivity. CTC 
enumeration will be performed in clinical laboratories with the CellSearch FDA-cleared 
assay. Molecular profiling in CTC will be performed in collaboration with core labs at 
MSK for isolation of CTC based on EpCAM expression, whole genome amplification of 
the DNA, and NextGen sequencing for copy number analysis, gene fusion and point 
mutation detection. In parallel, WBC from same patients are similarly analyzed to 
determine germline versus somatic mutations. The genomic alterations in prostate 
cancer specific genes will be confirmed by orthogonal molecular methods from RNA 
extracted from non-enriched blood samples collected in PAXgene tubes by an 
analytically validated orthogonal molecular method available in Clinical Chemistry at 
MSK.25 We plan to further explore this technology and approach within the context of 
this MLN0128 trial (See Appendix C: Circulating Tumor Cell (CTC) Laboratory Manual). 
 
Return of Genomic Data: It is possible that some patients whose tumors or blood are 
analyzed through investigational “next-generation” profiling will be found to have somatic 
or germline mutations in genes that are known to be associated with an increased risk of 
cancer or other diseases. It will not be possible to provide results of research tests not 
performed in a New York State Department of Health approved clinical laboratory. It will 
be stated in the consent that participants will be told that they will not receive any 
specific results from potential research tests. The consent will tell patients that if they 
wish to have genetic testing done for personal reasons than they should make an 
appointment with the MSKCC Clinical Genetics Service. If in the course of this research 
a research finding is obtained that may be critical to the preventive care of the 
participate or their family, as determined by procedures overseen by the IRB, those 


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participants who have consented to recontact to discuss research findings will be 
referred to the Clinical Genetics Service for consultation. 
 
3.3.3 FDG and FDHT PET imaging 
Developed as an AR-binding radiotracer, FDHT is an analog of DHT, the most prominent 
androgen at the tumor-tissue level in non-castrate subjects. As therapies have been 
developed that target AR, we have recognized the clinical need for (i) detecting 
pharmacodynamic changes caused by treatment with each class of drugs; (ii) 
developing an early indicator of response; and (iii) developing predictors of survival. 
 
Since securing an IND for FDHT at MSKCC, we have developed a paradigm of study 
using a combination of FDHT and FDG PET in close temporal proximity. Using this 
approach, we have studied more than 100 CRPC patients including follow-up after 
treatment (MSKCC protocol 00-095; PI Larson and Morris). This dual imaging approach 
has allowed us to classify individual prostate cancer lesions with respect to both 
metabolic phenotype (FDG PET) and AR status (FDHT), and thus we are beginning to 
understand how these tumor phenotypes correlate with and or determine therapeutic 
response. For the purposes of this trial, optional FDHT PET imaging will be performed at 
MSKCC under a separate PET acquisition protocol (MSKCC protocol 00-095). We 
propose to study both FDG and FDHT PET imaging at baseline and post-treatment (1 
week, 4 weeks, and at the time of progression), and to correlate the changes to test the 
following hypotheses: 
 
Since Akt activation causes increased transcription and plasma membrane localization 
of GLUT1, we hypothesize that comparing FDG-PET uptake immediately before and 
after treatment with MLN0128 will provide an early assessment of whether a given dose 
inhibits mTOR activity in tumor cells, independent of overall effects on tumor growth that 
might be evident weeks or months later. 
 
An increase in binding and uptake FDHT may occur when there is an escape through 
upregulation of AR.20 This may or may not be accompanied by increased FDHT uptake 
depending on the mechanism of tumor growth. 
 
3.4 
Rationale for conducting the study 
Drug development for castration-resistant prostate cancer (CRPC) has shifted focus from 
cytotoxic agents to the rational development of targeted approaches based on a 
fundamental understanding of disease biology. We have selected the mTORC1/2 kinase 
inhibitor MLN0128 because: (i) our published data indicate that mTORC1/2 is the most 
critical target in the PI3K pathway6; (ii) MLN0128 has the potential to overcome 
resistance seen with standard rapalogs through inhibition of  both TORC1 and TORC2; 
(iii) MLN0128 has been characterized in phase I studies that have revealed encouraging 
single agent activity. 
 
It is essential that we understand the effects of single agent mTOR inhibitors against 
different aspects of the malignant phenotype, so that we can comprehensively define the 
relevant pathways activated in response to MLN0128 and define rational therapeutic 
combinations on this basis. 


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We will therefore evaluate MLN0128 in this study with the goal of determining benefit as 
measured by progression-free survival. We also plan to explore mechanisms of 
sensitivity and resistance to this agent in men with metastatic CRPC using exploratory 
markers of response such as tumor biopsies, circulating tumor cells, and FDHT PET 
imaging. 
 
A daily dose of four milligrams (4mg QD) has been selected as the preferred dose and 
schedule for studies of MLN0128. 
 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.1 
Design 
Consented patients undergo a screening evaluation to determine eligibility (Figure 2). 
Eligible patients begin to receive daily MLN0128 beginning on Day 1 of Cycle 1. It is 
planned that each patient will receive continuous treatment in a 4-week dosing cycle, 
which will be discontinued at any time for documented disease progression, or 
unacceptable toxicity. Details regarding tumor evaluations, safety assessments and 
correlative studies are outlined in Section 9 and Section 10. 
 
Figure 2. Study schema 
 
Screening 
Day -30 to 
Day 1 
MLN0128 Dosing 
5mg po daily, continuous dosing 
28 days = 1 cycle 
 
 
 
 
End of 
Baseline 
Evaluation 
Day -14 to 
Day 1 
 
• Imaging 
• CTCs 
• PSA 
 
Cycle 1 
 
• Wkly clinic visit 
Week 4 only   
• PET imaging 
• Biopsy 
• CTCs 
Day 1 of 
each cycle 
• Clinic visit 
• CTCs 
• PSA 
Every 8 
weeks 
• Imaging 
 
Treatment 
Visit 
 
• Imaging 
• CTCs 
• PSA 
• PET imaging 
• Biopsy 
Follow -up 
30 days 
• PET imaging 
• Biopsy 
Biopsies are optional 
 
 
 
 
 
4.2 
Intervention 
 
4.2.1 Treatment Administration 
The Research Staff will provide each patient detailed instructions and training for the 
handling of study drug and administration to each patient at the beginning of the study. 
In general, the full prescribed dose of MLN0128 should be taken in the morning at 
approximately the same time each day. It is recommended that patients take their dose 
after a light meal and with 8 ounces of water. 


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4.2.2 Dosing Schedule 
MLN0128 will be given at a dose of 4mg daily po, continuously. A cycle will consist of 4 
weeks of treatment. 
 
The time of dose administration will be called “0” hour. If a patient vomits after receiving 
MLN0128, the dose should not be repeated. 
 
All patients who are enrolled in the study and receive a dose of MLN0128 are 
considered evaluable for toxicity. Additional subjects will be enrolled to replace any 
subjects who are enrolled, but do not receive treatment. 
 
4.2.3 Treatment Compliance 
All doses will be administered on an outpatient basis. Patients should report missed or 
partial doses of MLN0128 to the study site personnel and this should be recorded in the 
medical record with a reason for the incomplete dose. 
 
4.2.4 Re-treatment Criteria 
Patients will receive treatment until they meet any of the criteria for discontinuation listed 
in Section 13. 
 
4.2.5 Dose Modifications 
Patients will be monitored continuously for AEs while on study therapy. Patients will be 
instructed to notify their physician immediately for any and all toxicities. 
 
MLN0128 dosing should be withheld for ≥ Grade 2 renal insufficiency,  ≥ Grade 3 
MLN0128 possibly related hematologic or nonhematologic toxicities, or at the discretion 
of the investigator. If the event resolves to Grade ≤ 1 or baseline values within 14 days 
of interrupting therapy, the subject may resume study treatment at a dose reduction. 
 
See table of dose adjustments below according to the schedule applied in this protocol. 
 
If MLN0128 dosing is delayed for > 14 consecutive days for MLN0128-related toxicity 
despite supportive treatment per standard clinical practice or more than 2 dose 
reductions of MLN0128 is required in a subject, stop MLN0128 therapy, discontinue the 
subject from the study, and complete the follow-up visit within 30 days of the last 
administration of MLN0128. 
 
 
Table 1. Dose level modifications 
Dose Level 
Dose 
1 
4 mg QD 
-1 
3 mg QD 
-2 
Discontinue 
Level 1 is the starting dose. 
 
Any patient who’s treatment is interrupted for a toxicity that is related to study drug who 
does not re-start treatment after 14 consecutive days will be withdrawn from study 
treatment. 


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4.3 
Management of Clinical Events 
 
4.3.1 Management of Hyperglycemia 
In addition to obtaining fasting serum glucose (FSG) levels at clinic visits, all subjects will 
be given a glucometer to monitor their daily pre-dose fasting blood glucose (FBG) levels 
at home.  Subjects will be instructed to notify the study staff immediately with any 
abnormal readings (ie, ≥ 140 mg/dL) for further instructions on the management of their 
hyperglycemia.  Hyperglycemia observed during home glucose monitoring should be 
confirmed in the clinic. Investigators will be responsible for reviewing the home glucose 
monitoring logs for hyperglycemia.  If no irregularities in the fasting blood glucose level 
are observed during a minimum of 6 consecutive months, then the frequency of in-home 
fasting glucose testing may be reduced to twice weekly if the investigator approves. 
Subjects will continue to notify the investigator of fasting blood glucose levels that 
exceed 140 mg/dL and, if blood glucose levels are not well-controlled, or if the subject 
requires either oral hypoglycemic agents or insulin to control blood glucose levels, then 
the frequency of in-home testing of fasting blood glucose levels will be reinstated to 
daily. 
 
Guidance for MLN0128 dose management in the event of hyperglycemia is provided in 
the table below. 
 
 
 Table 3  
Management of Hyperglycemia  
Grade Description 
Treatment 
MLN0128 Dose Modification 
1 
Fasting blood 
sugar 
> ULN–160 
mg/dL 
Continue close monitoring 
of blood sugars. 
Initiate oral hypoglycemic 
agent. 
None 
2 
Fasting blood 
sugar 
> 160–250 
mg/dL 
Initiate oral hypoglycemic 
agent and/or insulin if not 
well controlled on oral 
agent. 
None 
≥3 
Fasting blood 
sugar 
> 250 mg/dL 
Initiate oral hypoglycemic 
agent and/or insulin. 
Hold drug until ≤ Grade 2. 
Resume MLN0128 based on 
timing of recovery: 
≤ 1 week: resume at same 
dose and schedule; 
>1 but ≤ 2 weeks:  reduce 
dose 
> 2 weeks:  stop MLN0128 and 
discontinue subject from the 
study. 
Prevention/Prophylaxis 
• 
Follow fasting serum glucose levels during clinic visits. 
• 
Monitor home glucometer test results. 
• 
Check HbA1c levels every 3 months during therapy. 


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• 
Life-style modifications, as appropriate (balanced diet, limit alcohol consumption, 
increase physical activity). 
• 
Most episodes of Grade 1 and 2 hyperglycemia respond quickly to oral metformin. 
• 
Early initiation of therapy is recommended to prevent higher grade hyperglycemia. 
• 
Fasting blood glucose levels ≥ 140 mg/dL by glucometer should be followed by 
closer monitoring of serum glucose and possible intervention. 
Abbreviations:  dL = deciliters; mg = milligrams; ULN = upper limit of normal. 
 
 
In the event that any FSG reading performed at the site indicates hyperglycemia (> 
upper limit of normal [ULN] or ≥ 110 mg/dL), the study staff should first ascertain that the 
subject was fasting at the time of the blood draw (ie, nothing by mouth for at least 8 
hours prior to blood being obtained), had continued to take their concomitant 
antiglycemic medications should the subject have underlying diabetes mellitus, and 
repeat the FSG as needed.  If the repeat FSG continues to demonstrate hyperglycemia, 
investigators should initiate steps to aggressively manage the hyperglycemia per 
standard clinical practice. The following guidelines are provided to aid the investigator in 
initiating antiglycemic therapies. 
 
Based on the clinical experience from MLN0128 trials, most episodes of hyperglycemia 
observed have been Grade 1 or 2 that have responded quickly to oral metformin. 
Hyperglycemia has not been dose-limiting since instituting a standard regimen for early 
treatment of hyperglycemia.  All subjects developing hyperglycemia on the study should 
have their glucose closely monitored by study staff. The investigator may choose either 
to continue close monitoring of subjects who develop Grade 1 hyperglycemia 
(FSG > ULN ≤ 160 mg/dL) or, alternatively, consider initiating treatment with an oral 
hypoglycemic agent, such as metformin.  All subjects with Grade ≥ 2 hyperglycemia 
(FSG > 160 mg/dL) must be treated aggressively with oral hypoglycemic agents and/or 
insulin as clinically indicated while continuing on MLN0128.  The investigator should 
consult an endocrinologist if needed to aid in optimizing the subject’s hyperglycemia 
treatment plan. 
 
It is recommended that subjects be treated initially with a fast acting, insulin sensitizer, 
such as metformin at 500 mg PO QD, and titrate up to a maximum of 1000 mg PO BID 
as needed.  Concurrent addition to metformin of DPP-4 inhibitors (eg, sitagliptin or 
vildagliptin) and/or insulin should also be considered. Oral sulfonylureas (eg, glipizide or 
glyburide) should be used with caution due to the higher risk of inducing hypoglycemia in 
subjects. The dose of oral hypoglycemic agents should be adjusted in subjects with 
renal insufficiency. 
 
4.3.2 Management of Noninfectious Pneumonitis 
Guidance for MLN0128 dose management in the event of noninfectious pneumonitis is 
shown in Table 4 table below.  Noninfectious pneumonitis has not been observed with 
MLN0128 as of December 2012. 
  
 
 
  Table 4  
Management of Non-infectious Pneumonitis  
 


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Grade Description 
Treatment 
MLN0128 Dose 
Modification 
1 
Asymptomatic: 
Radiographic findings 
only 
2 
Symptomatic: 
Not interfering with 
ADLs 
 
 
 
 
 
 
 
3 
Symptomatic: Interfering 
with ADLs; Requires 
administration 
of O2 
 
 
4 
Life-threatening: 
Ventilatory support 
indicated 
 
Rule out infection 
and closely monitor. 
 
 
Rule out infection 
and consider 
treatment with 
corticosteroids until 
symptoms improve 
to ≤ Grade 1. 
 
 
 
Rule out infection 
and consider 
treatment with 
corticosteroids until 
symptoms improve 
to ≤ Grade 1. 
Rule out infection 
and consider 
treatment with 
corticosteroids. 
None. 
 
 
 
Interrupt MLN0128 treatment: 
When symptoms ≤ Grade 1, 
re-initiate MLN0128 
treatment at a dose 
reduction 
Discontinue MLN0128 
treatment if failure to 
recover within 4 weeks. 
Discontinue MLN0128 
treatment. 
 
 
 
 
 
 
Discontinue MLN0128 
treatment. 
Abbreviations:  ADL = activities of daily living ; O2 = oxygen gas. 
 
 
4.3.3 Management of Hyperlipidemia 
Guidance for MLN0128 dose management in the event of hyperlipidemia is shown in the 
table below. 
 
 Table 5  
Management of Hyperlipidemia  
Grade Description 
Treatment 
MLN0128 Dose Modification 
1 
Cholesterol: 
> ULN - 300 mg/dL
Triglycerides: 
> 150 - 300 mg/dL 
None. 
None. 
2 
Cholesterol: 
> 300 – 400 mg/dL 
Triglycerides: 
> 300 - 500 mg/dL 
Treat hyperlipidemia 
according to standard
guidelines. 
Triglycerides ≥ 500 
mg/dl should be 
treated urgently due 
to risk of pancreatitis.
Maintain dose if tolerable. 
If toxicity becomes intolerable, 
interrupt MLN0128 dosing until 
recovery to ≤ Grade 1. 
Reinitiate at same dose. 
3 
Cholesterol: 
> 400 - 500 mg/dL 
Triglycerides: 
Same as for Grade 2.
Hold dose until recovery to ≤ 
Grade 1, then restart at a dose 
reduction 


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  Table 5  
Management of Hyperlipidemia  
 
 
Grade Description 
Treatment 
MLN0128 Dose Modification 
> 500 - 1000 mg/dL 
4 
Cholesterol: 
Same as for Grade 2. 
Discontinue treatment. 
> 500 mg/dL 
Triglycerides: 
> 1000 mg/dL 
Prevention/Prophylaxis 
• 
Life-style modifications, as appropriate (balanced diet, limit consumption of 
alcoholic beverages, increase physical activity). 
Abbreviations:  dL = deciliters; mg = milligrams; ULN = upper limit of normal. 
 
 
4.3.4 Management of Oral Mucositis 
Guidance for MLN0128 dose management in the event of oral mucositis is provided in 
the table below. 
  Table 6  
Management of Oral Mucositis  
 
 
Grade Description 
Treatment 
MLN0128 Dose Modification 
1 
Asymptomatic or 
mild symptoms 
 
 
 
 
 
 
 
2 
Moderate pain, not 
interfering with oral 
intake 
  
Modified diet 
indicated 
3 
Severe pain, 
interfering with oral 
intake 
 
4 
Life-threatening 
consequences 
Non-alcoholic mouth 
wash or 0.9% salt water 
rinse; 
Consider topical 
corticosteroids at 
earliest signs of 
mucositis. 
Topical analgesic mouth 
treatments; 
Topical corticosteroids; 
Initiate antiviral or 
antifungal therapy, if 
indicated. 
Same as for Grade 2; 
Consider intra-lesional 
corticosteroids. 
Same as for Grade 2. 
Consider intra-lesional 
corticosteroids. 
None. 
 
 
 
 
 
 
 
 
Maintain dose if tolerable. 
If toxicity becomes intolerable, 
interrupt MLN0128 dosing until 
recovery to ≤ Grade 1. 
Reinitiate at same dose. 
 
 
Hold dose until recovery to ≤ 
Grade 1, then restart at a dose 
reduction 
 
Discontinue treatment. 
  
Prevention/Prophylaxis 
• 
Consider initiation of a non- alcoholic mouth wash or 0.9% salt water rinses 4-6 
times daily with start of therapy before signs of mucositis develop. 
• 
Avoid using agents containing hydrogen peroxide, iodine, and thyme derivatives 
in management of stomatitis as they may worsen mouth ulcers. 


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4.3.5 Management of Rash 
Guidance for MLN0128 dose adjustment for the event of rash is provided in the table 
below. 
 
Table 7 
Management of Rash 
Grade Description 
Treatment 
MLN0128 Dose Modification 
 
≤ 2 
Macules/papules 
covering ≤ 30% body 
surface area with or 
without symptoms 
 
 
3 
Macules/papules 
covering > 30% body 
surface area with or 
without symptoms 
Consider treatment 
with topical steroid 
cream/ointment 
and/or oral anti- 
histamines. 
Consider treatment 
with topical steroid 
cream/ointment, 
oral anti-histamines, 
and/or pulsed 
steroids. 
None. 
  
 
 
 
 
Hold until ≤ Grade 2; 
Resume MLN0128 based on 
timing of recovery: 
≤ 2 weeks: reduce dose ; 
> 2 weeks: stop MLN0128 
and discontinue subject from 
the study. 
 
≥4 
Discontinue MLN0128 
treatment. 
 
 
 
4.3.6 Management of Nausea and/or Vomiting 
Guidance for MLN0128 dose adjustment for the event of nausea and/or vomiting is 
provided in the table below. 
 
 Table 8  
Management of Nausea and/or Vomiting  
Grade Description 
Treatment 
MLN0128 Dose Modification 
≤ 2 
Loss of appetite with or 
without decreased oral 
intake; 
1-5 episodes of vomiting
within 24 hours 
Maximize anti- 
emetic therapy; 
Consider IV fluid 
hydration. 
None. 
≥ 3 
Inadequate oral intake; 
≥ 6 episodes of vomiting
within 24 hours 
Maximize anti- 
emetic therapy; 
Initiate tube 
feeding, IVF, or 
TPN. 
Hold until ≤ Grade 1; 
Resume MLN0128 without 
dose modification. 
If toxicity continues despite 
optimal anti-emetic therapy 
for > 3 days: reduce dose. 
Prevention/Prophylaxis 
Prophylactic use of anti-emetic, anti-nausea, and anti-diarrheal medications are 
encouraged and may be used before each dose of MLN0128 as needed throughout the 
study. 
Abbreviations:  IV = intravenous; IVF = intravenous fluids; TPN = total parenteral nutrition 


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4.3.7 Management of Cardiac Events 
 
Management of Cardiac Instability 
For subjects showing signs of cardiac instability after MLN0128 dosing, additional 
monitoring onsite before clinic discharge should be considered. 
 
Management of Left Ventricular Dysfunction 
Guidance for MLN0128 dose adjustment for the event of left ventricular dysfunction is 
provided in the table below. 
  Table 9   
Management of Left Ventricular Dysfunction  
 
Grade Description 
MLN0128 Dose Modification 
1 
Asymptomatic decline in 
LVEF > 15% from baseline values 
OR; 
LVEF > 10%-15% from baseline 
values and is below institution’s LLN 
 
≥ 2 
Symptomatic cardiac 
dysfunction/congestive heart failure 
No change; continue MLN0128 at 
same dose and schedule. 
 
 
 
 
 
Discontinue treatment. 
Abbreviations:  LLN = lower limit of normal; LVEF = left ventricular ejection fraction. 
 
Management of QTc Prolongation 
Guidance for MLN0128 dose adjustment for the event of QTc prolongation is provided in 
the table below. 
 
 Table 10  
Management of QTc Prolongation  
Grade Description Treatment 
MLN0128 Dose Modification 
2 
480 ms < 
QTc 
< 501 ms 
Evaluate for other possible 
causes (eg, electrolyte 
disturbance, concomitant 
medication, etc.) 
None; continue MLN0128 at 
the same dose and schedule. 
≥ 3 
QTc ≥ 501 
ms 
Evaluate for other possible 
causes (eg, electrolyte 
disturbance, concomitant 
medication)a; 
Consider a formal consult by a 
cardiologist; 
Notify the study doctor; 
Additional ECGs may be 
performed at intervals that the 
treating physician deems 
clinically appropriate until 
repeated QTc measurements 
fall or are below the threshold 
interval that triggered the 
repeat measurement. 
MLN0128 should be 
interrupted. 
The decision whether to 
reinitiate MLN0128 treatment 
with or without dose reduction 
and additional monitoring in 
those subjects who had 
asymptomatic prolonged QTc ≥ 
501 msec (Grade 3) that has 
reverted to an acceptable 
interval, have previously 
tolerated MLN0128, and 
appear to have benefitted from 
MLN0128 treatment with either 
disease control or response, 
will be agreed to by the 


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investigator and the study 
doctoron a case-by-case basis. 
Abbreviations:  ECG = electrocardiogram; IV = intravenous; ms = milliseconds; QTc = QT 
interval corrected for heart rate 
a A list of medications known to prolong QTc can be found at www.torsades.org and 
www.QTdrugs.org. 
 
See Section 10.4 
Cardiac Function for instructions regarding ECG acquisition and 
review. 
 
4.3.8 Management of Other Toxicities 
Guidance for MLN0128 dose management in the event of nonhematologic and 
hematologic toxicities is shown in the tables below. 


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Table 11 
Management of Other Nonhematologic Toxicities 
  (including asthenia/weakness)  
 
MLN0128 Dose 
Grade Description 
Treatment 
1 
Mild:  Asymptomatic or mild 
symptoms; clinical or 
diagnostic observations 
only; intervention not 
indicated 
Modification 
If tolerable, no adjustment 
required. 
2 
Moderate:  minimal, local, or 
non-invasive intervention 
indicated 
 
 
 
 
 
 
 
 
 
 
 
 
 
3 
Severe or medically 
significant but not 
immediately life-threatening; 
hospitalization or 
prolongation of 
hospitalization indicated 
 
 
 
 
 
4 
Life-threatening 
consequences – urgent 
intervention required 
Initiate 
appropriate 
medical therapy 
and monitor. 
If tolerable, no adjustment 
required. 
If toxicity becomes 
intolerable, interrupt 
MLN0128 dosing until 
recovery to ≤ Grade 1. 
Reinitiate at same dose 
level. 
If toxicity recurs at Grade 2, 
interrupt MLN0128 dosing 
until recovery to ≤ Grade 1. 
Reinitiate at a dose 
reduction. 
Interrupt MLN0128 treatment 
until symptoms resolve to ≤ 
Grade 1. 
Re-initiate MLN0128 
treatment at a dose 
reduction 
If toxicity recurs at Grade 3, 
discontinue MLN0128 
treatment. 
Discontinue MLN0128 
treatment. 


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Table 12 
Management of Other Hematologic Toxicities 
(for clinically significant laboratory values only) 
 
 
Grade Description 
Treatment 
1 
Mild 
Monitor as 
necessary 
MLN0128 Dose 
Modification 
No adjustment required. 
2 
Moderate: intervention may 
be indicated 
 
 
 
 
 
 
 
 
 
 
 
 
3 
Severe or medically 
significant but not 
immediately life-threatening: 
hospitalization or 
prolongation of 
hospitalization may be 
indicated 
 
 
 
4 
Life-threatening 
consequences: urgent 
intervention required 
Initiate 
appropriate 
medical therapy 
as necessary 
and monitor. 
 
 
 
 
 
 
 
 
Initiate 
appropriate 
medical therapy 
as necessary 
and monitor. 
 
 
 
 
 
 
Initiate 
appropriate 
medical therapy 
as necessary 
and monitor. 
No adjustment required. 
Interrupt MLN0128 dosing 
at investigator discretion. 
Reinitiate at same dose 
level. 
If toxicity recurs at Grade 2, 
interrupt MLN0128 dosing 
until recovery to ≤ Grade 1. 
Reinitiate at a dose 
reduction at investigator 
discretion. 
Interrupt MLN0128 treatment 
until resolved to ≤ Grade 1 or 
baseline. 
Re-initiate MLN0128 
treatment at a dose 
reduction 
If toxicity recurs at Grade 3, 
discontinue MLN0128 
treatment. 
Discontinue MLN0128 
treatment. 
 
 
4.4 
Concomitant Medications 
All concomitant medications administered to the patient will be reported from the first 
day of Study Drug administration through 4 weeks following receipt of the last dose of 
Study Drug. Drug name, start and stop dates will be recorded. Drug doses, dose 
changes, frequency, and routes of administration will not be reported. Missed doses will 
not be considered stop dates unless the drug has been discontinued. 
 
4.4.1 Supportive care medications 
Supportive care medications are permitted with their use following institutional 
guidelines. 
 
The following supportive care medications are considered permissible during the study: 
 
• 
Conventional multivitamins, selenium and soy supplements 
• 
Additional systemic glucocorticoid administration such as “stress dose” 
glucocorticoid is permitted if clinically indicated for a life threatening medical 


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condition, and in such cases, the use of steroids will be documented as concomitant 
drug 
 
4.4.2 Prohibited therapies 
No other chemotherapy, hormonal therapy, immunotherapy, or experimental anti-cancer 
medications will be permitted while the patient is on treatment with MLN0128. Patients 
who have not undergone surgical orchiectomy must continue on medical therapies (i.e., 
gonadotropin releasing hormone analogs [GnRH analogs] to maintain castrate levels of 
serum testosterone). Any disease progression requiring other forms of specific anti- 
tumor therapy will be cause for discontinuation from the study. 
 
4.4.3 Restricted therapies 
 
 
 
Symptomatic antiemetics may be administered at the Investigator’s discretion; however, 
they should not be administered within 2 hours of any scheduled pharmacokinetic 
sample collection. Palliative and supportive care for disease-related symptoms will be 
offered to all patients on this trial. Details of interventions (e.g., analgesic use, 
paracentesis, etc.) will be collected on the case report form. 
 
In certain instances, focal radiation therapy for palliation of bone disease-related 
symptoms might be allowable after discussion between the Principal Investigator and 
the Investigator. The need for radiation therapy will generally be considered indicative of 
progressive disease. Patients on stable doses of bisphosphonates for palliation of bone 
metastases may continue on this medication. Patients are not allowed to initiate 
bisphosphonate therapy immediately prior to or during the study. 
 
Colony-stimulating factors (i.e., G-CSF, GM-CSF, erythropoietin-stimulating agents, etc.) 
should not be administered prophylactically during the study period. However, 
interventional use of myeloid growth factor may be used in the case of febrile 
neutropenia, at the discretion of the Investigator. Growth factor use must be consistent 
with the product label. 
 
Strong CYP3A4, CYP2C9, and CYP2C19 inhibitors and inducers should be avoided. If a 
patient requires treatment with one or more of  the strong inhibitors or inducers, 
alternatives with a reduced potential to inhibit or induce these enzymes should be 
considered. If a suitable alternative does not exist or is not appropriate, strong CYP3A4, 
CYP2C9, and CYP2C19 inhibitors and inducers should be used with caution. Examples 
of strong CYP3A4, CYP2C9, and CYP2C19 inhibitors and inducers can be found in 
Appendix H: Strong Inhibitors and Inducers of CYP2C9, CPY2C19, and CYP3A4. 
 
4.4.4 Washout periods for prohibited medications 
 
 
 
Prohibited medications, such as bicalutamide, or flutamide, should be discontinued 4 
weeks prior to Week 1 Day 1 in accordance with the standard of care suggested in 
guidelines published by the Prostate Cancer Working Group 2 (PCWG2).21   The decision 
to administer a prohibited drug/treatment should be made based on the consideration of 


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the safety of study participant. Patients who require the use of any of these agents will 
be discontinued from study treatment. 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
 
5.1 
Pharmacology 
 
MLN0128 will be supplied in tamper-resistant bottles as capsules containing 1 of 3 dose 
strengths. 
 
• 
MLN0128 capsules, 1 mg - white opaque color 
 
• 
MLN0128 capsules, 3 mg – orange opaque color; and/or 
 
• 
MLN0128 capsules, 5 mg – grey opaque color 
 
Each 1-, 3-, and 5-mg capsule for oral administration contains 1, 3, and 5 of MLN0128, 
respectively in addition to the following inactive ingredients: microcrystalline cellulose 
(solid filler/diluents), magnesium stearate (lubricant), and hard gelatin capsule. 
 
5.2 
Packaging and Labeling 
MLN0128 drug product is packaged in high-density polyethylene (HDPE), white, 
opaque, round, tamper- and child-resistant bottles in counts (Ct) of 30 capsules. 
MLN0128 will be packaged and labeled according to all regulations. Sites must store 
according to the labeled conditions. 
 
5.3 
Storage and Accountability 
 
5.3.1 Storage requirements 
 
MLN0128 should be stored at controlled room temperature 15°C to 30°C (59°F to 86°F). 
All study supplies must be kept in a restricted access area. Accountability for MLN0128 
at all study sites is the responsibility of the sponsor-investigator. 
 
5.3.2 Drug dispensing log and pill diary 
Study site personnel will record all study drugs administered during this trial on the drug- 
dispensing log. 
 
The drug dispensing log will contain the following information: 
 
• 
patient study identification number 
• 
date(s) of study drug administered 
• 
quantities of study drug administered 
• 
signature of the investigator 
 
Subjects will be provided with a diary in which to record their intake of study drug 
(Appendix E: Pill Diary). However, the actual number of tablets taken by the subject 
must be calculated from the number of tablets dispensed and returned. 


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6.0 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
Target Population 
Men with CRPC who have received either enzalutamide and/or abiraterone but have no 
prior exposure to PI3K/mTOR pathway inhibitors. 
 
6.1 
Subject Inclusion Criteria 
To be included in this study, patients should have histologically confirmed castration- 
resistant metastatic prostate cancer with evidence of disease progression. Patients must 
have been in a castrate state either by orchiectomy or by GnRH analogues. In detail, 
they should meet all of the following criteria: 
 
1. 
Histologically confirmed prostate cancer with progressive metastatic disease 
based on any of the following: i) a rise in PSA, ii) transaxial imaging, or iii) 
radionuclide bone scan. 
 
a. 
PSA - a minimum of 3 consecutive rising levels, with an interval of ≥ 
1 week between each determination. The last determination must 
have a minimal value of ≥ 2 ng/mL and be determined within two 
weeks prior to enrollment. 
 
b. 
Measurable Disease - patients showing new or progressive soft 
tissue masses on CT or MRI scans as defined by the PCWG2 
criteria21 
 
c. 
Radionuclide bone scan – at least two new metastatic lesions. 
 
2. 
Detectable metastases by bone scan, CT-scan or MRI. 
 
3. 
Ongoing androgen depletion therapy with a Gonadotropin Releasing Hormone 
(GnRH) analogue or inhibitor, or orchiectomy (i.e., surgical or medical castration). 
For patients who have not had an orchiectomy, there must be a plan to maintain 
effective GnRH-analogue therapy for the duration of the trial. 
 
4. 
Castrate levels of serum testosterone < 50 ng/dL determined within 4 weeks prior 
to starting treatment. 
 
5. 
Patients who are receiving an anti-androgen as part of their first-line hormonal 
therapy must have shown progression of disease off the anti-androgen prior to 
enrollment. 
 
6. 
Patients must have received treatment with either enzalutamide and/or 
abiraterone prior to study entry. 
 
7. 
At least 4 weeks must have elapsed from the use of androgen receptor 
antagonists (i.e., flutamide, nilutamide, bicalutamide, enzalutamide); 5-α 
reductase inhibitors (i.e., finasteride, aminoglutethimide); abiraterone acetate; 
estrogens; nitrosoureas, mitomycin C, isotype therapy, ketoconazole, 
chemotherapy and other anti-cancer pharmacologic therapy prior to beginning 
protocol therapy. 


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8. 
At least 8 weeks must have elapsed from the use of Strontium-89, Radium-223, 
Samarium-153, or immunotherapy (e.g., Provenge) prior to beginning protocol 
therapy. 
 
9. 
At least 4 weeks must have elapsed from the use of any investigational agent 
prior to beginning protocol therapy. 
a. 
Note: Prior treatment with PI3K/mTOR pathway inhibitors prohibited. 
 
10. 
At least 4 weeks must have elapsed from major surgery. 
 
11. 
Toxicities related to prior therapy must either have returned to ≤ Grade 1, 
baseline or deemed irreversible. 
 
12. 
Patients with treated, non-progressive epidural disease are eligible. 
 
13. 
KPS performance status 70-100% (Appendix A: Performance Status Criteria) 
 
14. 
At least 18 years of age, with a life expectancy at least 3 months. 
 
15. 
Patient must be willing to comply with study procedures. 
 
16. 
Physical and laboratory test findings 
 
a. 
Adequate hepatic function with serum bilirubin ≤ 1.5 times the upper 
institutional limits of normal (ULN), ALT and AST ≤ 2.5 x ULN. 
Patients with a history of Gilbert’s syndrome may be enrolled if the 
total bilirubin is < 3 mg/dL with a predominance of indirect bilirubin 
 
b. 
Adequate renal function with serum creatinine ≤ 1.5 x ULN. 
 
c. 
Adequate hematologic function with absolute neutrophil counts ≥ 
1,500 cell/mm3 and platelets ≥ 100,000 cells/mm3 and hemoglobin 
value ≥ 9 g/dL (Note: patients whose anemia has been corrected to a 
hemoglobin value ≥ 9 g/dL with blood transfusions are allowed). 
 
d. 
Electrolytes (including potassium, sodium, and serum calcium 
corrected for albumin or ionized calcium) must be within normal 
limits. 
 
17. 
Left ventricular ejection fraction (LVEF)  no more than 5 absolute percentage 
points below the institutional standard of normal as measured by echocardiogram 
(ECHO) or multiple gated acquisition scan (MUGA) within 4 weeks prior to first 
study drug administration (ie, if the institutional normal is 50%, subject’s LVEF 
may be as low as 45% to be eligible for the study) 
 
6.2 
Subject Exclusion Criteria 
Patients that meet any of the criteria listed below will not be eligible for study entry: 
 
1. 
History of, or current known metastases in the brain or untreated spinal cord 
compression; 


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2. 
History of another malignancy within the previous 2 years except for the 
following: 
 
a. 
Adequately treated basal cell or squamous cell skin cancer, 
superficial bladder cancer, 
 
b. 
Adequately treated Stage I or II cancer currently in complete 
remission, or any other cancer that has been in complete remission 
for at least 2 years; 
 
3. 
Prior treatment with PI3K/mTOR pathway inhibitors; 
 
4. 
Diabetes mellitus on active treatment, or subjects with either of the following: 
 
a. Fasting blood glucose (FBG) ≥ 126 mg/dL (7.0 mmol/L), or 
 
b. HbA1c ≥ 6.5%; 
 
5. 
Use of herbal products that may decrease PSA levels (i.e., saw palmetto) or 
systemic corticosteroid greater than the equivalent of 10 mg of prednisone per 
day during the 4 weeks prior to screening or plans to initiate treatment with the 
above during the entire duration of the study; 
 
6. 
Any history of unstable angina, myocardial infarction, New York Heart 
Association (NYHA) Class III or IV heart failure (See Appendix G: New York 
Heart Association Classification of Cardiac Disease), and/or pulmonary 
hypertension; 
 
7. 
Significant active cardiovascular disease including: 
 
a. 
Uncontrolled high blood pressure (ie, systolic blood pressure > 180 
mmHg, diastolic blood pressure > 95 mmHg) 
 
b. 
Grade 3 or higher valvular disease 
c. 
Grade 3 or higher atrial fibrillation 
d. 
Grade 3 or higher bradycardia 
e. 
Endocarditis 
 
f. 
Pulmonary embolism 
 
g. 
Recent cerebrovascular accident within 6 months prior to enrollment 
 
8. 
A requirement for positive inotropic support (excluding digoxin) or serious 
uncontrolled cardiac arrhythmia (including atrial flutter/fibrillation) within 1 year 
prior to screening 
 
9. 
A pacemaker or implantable cardiac defibrillator 
 
10. 
Known history of infection with human immunodeficiency virus (HIV), based on 
medical history (screening labs to rule out HIV infection are not required); 


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11. 
Any other condition that, in the opinion of the Investigator, would impair the 
patient’s ability to comply with study procedures. 
 
 
 
7.0 
RECRUITMENT PLAN 
 
Patients will be recruited through outpatient clinics. Potential research subjects will be 
identified by a member of the patient’s treatment team, the protocol investigator, or the 
research team. Study investigators will discuss the details of the study and enrollment 
with their patients as part of the recruitment process. Patients will be required to sign a 
statement of informed consent that meets the requirements of the IRB of this center. The 
medical record will include a statement that written informed consent was obtained. No 
women will be included in this study, which addresses treatment of prostate cancer. 
 
Subjects will be enrolled without respect to race or ethnicity. This study will be 
conducted in accordance with the ethical principles that have their origin in the current 
Declaration of Helsinki and will be consistent with International Conference on 
Harmonization Good Clinical Practice (ICH GCP) and applicable regulatory 
requirements. 
 
8.0 
PRETREATMENT EVALUATION 
 
8.1 
Screening (Day -30 to Day 1) 
The screening visit will determine patient eligibility according to the inclusion and 
exclusion criteria (Sections 6.1 
Subject Inclusion Criteria and 6.2 
Subject 
Exclusion Criteria). The following assessments will be performed at this visit: 
 
•  Obtain informed consent and research authorization 
•  Obtain histologic and radiologic confirmation of disease 
•  Record medical history (including prior treatment for prostate carcinoma) 
•  Conduct physical exam (KPS performance status, vital signs, HEENT, 
height/weight) 
•  Echocardiogram or MUGA scan 
•  Toxicity/AE assessment 
•  Discuss concurrent medications 
•  Perform 12-lead ECG 
•  Radionuclide bone scan 
•  FDG PET with contrast (if feasible) 
•  FDHT PET (Optional—on protocol 00-095) 
•  Tumor biopsy (Optional) 
 
8.2 
Baseline Evaluation (Day -14 to Day 1) 
A visit within 14 days prior to initiation of protocol therapy will further determine patient 
eligibility and collect baseline patient data. The visit must include the assessments listed 
below: 
 
•  Laboratory testing (All components of Table 13) 
•  CTCs 


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9.0 
TREATMENT/INTERVENTION PLAN 
 
9.1 
Cycle 1, Week 1 (Day 1) 
•  Interim medical history 
•  Physical exam and vital signs 
•  Assess KPS performance status 
•  Blood samples for laboratory tests:  hematology, serum chemistry, PSA (see 
Table 13) and CTCs 
•  Toxicity/AE assessment 
•  Discuss concurrent medications 
•  Patient to monitor daily fasting blood glucose level at home 
•  ECG pre dose, 2 hours post dose (+/- 15 minutes), and 4 hours post dose (+/- 
15 minutes) 
•  Urinalysis 
 
9.2 
Cycle 1, Week 2 (Day 8±1 day) 
•  Interim medical history 
•  Physical exam and vital signs 
•  Assess KPS performance status 
•  Blood samples for laboratory tests:  hematology and serum chemistry (see 
Table 13) 
•  Toxicity/AE assessment 
•  Discuss concurrent medications 
•  Patient to monitor daily fasting blood glucose level at home 
•  ECG 2 hours post dose (+/- 15 minutes) 
 
9.3 
Cycle 1, Week 3 (Day 15±1 day) 
•  Interim medical history 
•  Physical exam and vital signs 
•  Assess KPS performance status 
•  Blood samples for laboratory tests:  hematology and serum chemistry (see 
Table 13) 
•  PT, PTT, INR 
•  Toxicity/AE assessment 
•  Discuss concurrent medications 
•  Patient to monitor daily fasting blood glucose level at home 
•  ECG 2 hours post dose (+/- 15 minutes) 
•  Urinalysis 
 
9.4 
Cycle 1, Week 4 (Day 22±1 day) 
•  Interim medical history 
•  Physical exam and vital signs 
•  Assess KPS performance status 
•  Blood samples for laboratory tests:  hematology and serum chemistry (see 
Table 13) 
•  Toxicity/AE assessment 
•  Discuss concurrent medications 
•  FDG PET (± 7 days) 
•  FDHT PET (Optional—on protocol 00-095) (± 7 days) 


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• 
• 
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Discuss concurrent medications 
Patient to monitor daily fasting blood glucose level at home
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•  Tumor Biopsy (Optional) (± 7 days) 
•  Patient to monitor daily fasting blood glucose level at home 
•  ECG 2 hours post dose (+/- 15 minutes) 
 
9.5 
Cycle 2, Week 1 (Day 1±2 day) 
•  Interim medical history 
•  Physical exam and vital signs 
•  Assess KPS performance status 
•  Blood samples for laboratory tests:  hematology, serum chemistry, PSA (see 
Table 13) and CTCs 
•  Toxicity/AE assessment 
•  Discuss concurrent medications 
•  Patient to monitor daily fasting blood glucose level at home 
•  ECG pre dose and 2 hours post dose (+/- 15 minutes) 
•  Urinalysis 
 
9.6 
Cycle 2, Week 2 (Day 8±2 day) 
•  Interim medical history 
•  Physical exam and vital signs 
•  Assess KPS performance status 
•  Blood samples for laboratory tests:  hematology and serum chemistry (see 
Table 13) 
•  Toxicity/AE assessment 
•  Discuss concurrent medications 
•  Patient to monitor daily fasting blood glucose level at home 
•  ECG 2 hours post dose (+/- 15 minutes) 
 
9.7 
Cycle 2, Week 3 (Day 15±2 day) 
•  Interim medical history 
•  Physical exam and vital signs 
•  Assess KPS performance status 
•  Blood samples for laboratory tests:  hematology and serum chemistry (see 
Table 13) 
•  PT, PTT, INR 
•  Toxicity/AE assessment 
•  Discuss concurrent medications 
•  Patient to monitor daily fasting blood glucose level at home 
•  ECG 2 hours post dose (+/- 15 minutes) 
•  Urinalysis 
 
9.8 
Cycle 2, Week 4 (Day 22±2 day) 
•  Interim medical history 
•  Physical exam and vital signs 
•  Assess KPS performance status 
•  Blood samples for laboratory tests:  hematology and serum chemistry (see 
Table 13) 


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• 
• 
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Discuss concurrent medications 
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•  ECG 2 hours post dose (+/- 15 minutes) 
 
9.9 
Cycle 3, Week 1 (Day 1±2 day) 
•  Interim medical history 
•  Physical exam and vital signs 
•  Assess KPS performance status 
•  Blood samples for laboratory tests:  hematology, serum chemistry, PSA (see 
Table 13) and CTCs 
•  Imaging assessments (contrast-enhanced CT [if feasible], radionuclide bone 
scan) (± 7 days) 
•  Toxicity/AE assessment 
•  Discuss concurrent medications 
•  Patient to monitor daily fasting blood glucose level at home 
•  Urinalysis 
•  HbA1c 
 
9.10 
Cycle 3, Week 3 (Day 15±2 day) 
•  Interim medical history 
•  Physical exam and vital signs 
•  Assess KPS performance status 
•  Blood samples for laboratory tests:  hematology and serum chemistry (see 
Table 13) 
•  PT, PTT, INR 
•  Toxicity/AE assessment 
•  Discuss concurrent medications 
•  Patient to monitor daily fasting blood glucose level at home 
•  Urinalysis 
 
9.11 
Cycle 4, Week 1 (Day 1±2 day) 
•  Interim medical history 
•  Physical exam and vital signs 
•  Assess KPS performance status 
•  Blood samples for laboratory tests:  hematology, serum chemistry, PSA (see 
Table 13) and CTCs 
•  Toxicity/AE assessment 
•  Discuss concurrent medications 
•  Patient to monitor daily fasting blood glucose level at home 
•  Urinalysis 
 
9.12 
Cycle 4, Week 3 (Day 15±2 day) 
•  Interim medical history 
•  Physical exam and vital signs 
•  Assess KPS performance status 
•  Blood samples for laboratory tests:  hematology and serum chemistry (see 
Table 13) 
•  PT, PTT, INR 


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•  Urinalysis 
 
9.13 
Cycle 5 through end of treatment 
The following evaluations will be performed on Day 1 (±2 days) of each 4-week cycle: 
 
•  Interim medical history 
•  Physical exam and vital signs 
•  Assess KPS performance status 
•  Blood samples for laboratory tests:  hematology, serum chemistry, PSA (see 
Table 13)  and CTCs 
•  Toxicity/AE assessment 
•  Discuss concurrent medications 
•  Urinalysis 
•  HbA1c (Cycle 6 and every 3 cycles afterwards) 
•  PT, PTT, INR 
•  Patient to monitor daily fasting blood glucose level at home for the first 6 
months, then 2 times weekly.  If changes to metformin dose, then patient 
should resume daily fasting blood glucose level at home 
 
9.14 
Every 8 weeks (± 7 days) 
The following evaluations will be performed every 8 weeks: 
 
 
•  Imaging assessments (contrast-enhanced CT [if feasible], radionuclide bone 
scan) (± 7 days) 
 
9.15 
End-of-treatment visit 
Within 28 days of the last dose of study medication the following study activities will 
occur: 
 
•  Blood samples for laboratory tests:  hematology, serum chemistry, PSA (see 
Table 3)  and CTCs 
•  Toxicity/AE assessment 
•  Discuss concurrent medications 
•  Radionuclide bone scan (± 7 days, unless performed in the 30 days prior) 
•  FDG PET with contrast (if feasible) (± 7 days) 
•  FDHT PET (Optional on protocol 00-095) (± 7 days) 
•  Tumor Biopsy (Optional) (± 7 days) 
•  ECG 
 
9.16 
Follow-up (30 days or until death) 
Patients will be followed for at least 30 days after removal from treatment or until death. 
Patients withdrawn from the study because of AEs will be followed until the AE has 
either resolved or stabilized. Reasons for premature withdrawal should be determined 
and noted. 
 
10.0 EVALUATION DURING TREATMENT/INTERVENTION 
 
A tabular schedule of assessments is provided in Appendix B: Study Calendar. 
The following assessments and procedures will occur during the study. 


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10.1 
Medical History 
Medical history, such as previous treatments, procedures, and conditions will be 
collected during the screening period. Record demographics. 
 
10.2 
Physical Examination 
Evaluations should be performed by the same evaluator throughout the study whenever 
possible. 
 
Physical examination includes HEENT (head, eyes, ears, nose, and throat), chest, 
cardiac, abdominal, extremities, neurologic, and lymph node examinations. Weight will 
be recorded at every visit. Height will be recorded at screening visit only. 
 
Vital signs include upright blood pressure, heart rate, respiratory rate, and oral or aural 
body temperature. 
 
10.3 
Performance Status 
Performance status will be assessed using KPS performance status criteria as outlined 
in Appendix A: Performance Status Criteria. 
 
10.4 
Cardiac Function 
To assess cardiac function at baseline, a 12-lead ECG should be obtained. Hypokalemia 
should be corrected prior to ECG collection. 
 
Acquisition of 12-Lead Electrocardiograms 
 
All scheduled ECGs should be performed after the patient has rested quietly for at least 
5 minutes in a supine position.  In some cases, it may be appropriate to repeat an 
abnormal ECG to rule out improper lead placement as contributing to the ECG 
abnormality. 
 
Review of 12-Lead Electrocardiograms 
 
To ensure safety, a qualified individual at the site will review any clinically significant 
ECG abnormalities, including confirmation that the machine-estimates of the QTc are 
accurate using the appropriate QT correction formula.  In the event that a QTc value 
confirmed by the qualified reader is > 480 msec, an evaluation should be conducted to 
correct other possible causes (eg, electrolyte disturbance, concomitant medication, etc.). 
A list of medications known to prolong QTc can be found at www.torsades.org and 
www.QTdrugs.org.  If done prior to protocol enrollment and if a repeat ECG meets 
eligibility requirements, the patient may enroll to the study upon review and agreement 
by the study doctor. 
 
Review of Clinically Significant Electrocardiographic Abnormalities 
 
In the event that a QTc value confirmed by the qualified reader is > 500 msec for any 
ECG, the following will occur: 
 
• 
MLN0128 should be interrupted and an evaluation should be conducted to correct 
other possible causes (eg, electrolyte disturbance, concomitant medication). 


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• 
A formal consult by a cardiologist should be considered.  Additional ECGs may be 
performed at intervals that the treating physician deems clinically appropriate until 
repeated QTc measurements fall are below the threshold interval that triggered the 
repeat measurement. 
 
 
 
 
The decision on whether to reinitiate MLN0128 treatment with or without dose reduction 
and additional monitoring in those patients who had asymptomatic prolonged QTc > 500 
msec (Grade 3) that has reverted to an acceptable interval, have previously tolerated 
MLN0128, and appear to have benefitted from MLN0128 treatment with either disease 
control or response, will be determined on a case-by-case basis. 
 
 
10.5 
Clinical Laboratory Tests 
 
10.5.1 Laboratory parameters 
Clinical laboratory tests will include the following (Error! Reference source not 
found.13): 
 
Table 13. List of laboratory tests 
Hematology: 
- Hematocrit (Hct) 
- Hemoglobin (Hgb) 
- Platelet count (PLT) 
- Red blood cell (RBC) count 
- White blood cell (WBC) count with 
differential 
Coagulation Factors: 
- Prothrombin Time (PT) 
- Partial Thromboplastin Time (PTT) 
- International Normalized Ratio 
(INR) 
 
Serum Chemistry (Fasting): 
- Alkaline phosphatase (ALK-P) 
- Alanine aminotransferase (ALT; SGPT) 
- Aspartate aminotransferase (AST; SGOT) 
- Blood urea nitrogen (BUN) 
- Carbon dioxide (CO2) 
- Chloride (Cl) 
- Creatinine (Cr) 
- Glucose (Glu) 
- Lactate Dehydrogenase (LDH) 
- Magnesium (Mg) 
- Potassium (K) 
- Sodium (Na) 
- Total bilirubin 
- Lipid Profile 
Additional laboratory tests: 
- Prostate specific antigen (PSA) 
- Serum testosterone (T), 
  
- HbA1c  
 
 
10.5.2 Sample collection, storage and shipping 
Local laboratories will analyze all hematology, blood chemistry collected for the study. 
Samples will be analyzed at a facility meeting Clinical Laboratory Improvement 
Amendments (CLIA) requirements and/or using methods documented in a methods 
validation report. 
 
10.6 
Efficacy Assessments 
Progression-free survival (PFS) at 6 months from the start of treatment, as defined by 
the Prostate Cancer Working Group 2 (PCWG2) guidelines (primary endpoint measure). 


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10.7 
Tumor Biopsies 
With agreement of the investigator and sponsor, and with the patient’s consent, paired 
tumor tissue samples (including bone lesions in subjects with bone metastases) may be 
collected during Screening , at Week 4 (± 7 days) and at End of Treatment (± 7 days). 
Tumor samples at Week 4 can be collected either pre- or post-dose. Image-guided 
biopsies will be performed after the patient’s prior imaging is reviewed and target lesions 
are identified for biopsy. Lesions will be chosen based upon the strength of the evidence 
suggesting the presence of metastasis so as to minimize patient risk. Sample types may 
include surgical biopsies, core needle biopsies, fine needle aspirates or punch biopsies, 
where applicable. Collection of tumor fluid samples (confirmed as malignant by a 
cytopathologist) may also be considered on a case-by-case basis. The sample type 
should be kept consistent per patient for paired tissue collection whenever feasible. 
 
Tissue samples may be utilized for organoid growth, morphologic assessment, percent 
tumor involvement (if applicable), and immunohistochemistry depending on the amount 
of specimen that can be safely and feasibly collected. Providing adequate tissue is 
available, samples will be evaluated for downstream indicators of PI3K pathway 
modulation and additional pathways of interest. Specific markers may include: pS6K, 
p4EBP1, pAKT, AR and PHLPP 1 and 2. The analysis will be performed under the 
guidance of Dr. Victor Reuter, and members of the MSKCC genitourinary pathology staff 
will score both staining intensity and the percentage of positive cells exhibiting 
immunoreactivity (as a continuous variable). Intensity will be scored in a 4-point scale (0- 
3). The percentage of cells with weak (1), moderate (2) and strong (3) staining will also 
be recorded allowing us to establish an H-score. The H-score is the sum of percentages 
of positive cells in each of 3 intensity categories with a scale ranging from 0-300. In 
addition, all cases will be digitally scanned and the staining parameters will be evaluated 
using the Aperio signal quantification software. 
 
10.8 
Circulating Tumor Cell Studies 
  
 
The CTC number will be measured at baseline, Day 1 of each cycle, and at the time of 
progression (end-of-treatment) using an FDA-cleared analytically validated semi- 
automated system, CellSearch (Veridex, LLP) in the CLIA certified laboratory of Dr. 
Martin Fleisher at MSKCC. Currently, we use the EpCAM-based immunomagnetic 
enriched CTC sample to analyze the AR, TMPRSS2-ERG and PTEN by FISH, after 
fixing the cells into the enumeration chambers (Neon, Veridex). After hybridization, the 
chambers are re-interrogated for genomic abnormalities in the previously identified CTC. 
We are prospectively testing the predictive value of genomic alterations in AR, 
TMPRSS2-ERG and PTEN by FISH in CTC isolated by CellSearch EpCAM- 
immunomagnetic enrichment, and sensitivity to treatment with AR targeted agents such 
as ARN-509 and we plan to further explore this technology and approach within the 
context of this MLN0128 trial. 
 
Molecular profiling in CTC will be performed in collaboration with core labs at MSK for 
isolation of CTC based on EpCAM expression, whole genome amplification of the DNA, 


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and NextGen sequencing for copy number analysis, gene fusion and point mutation 
detection. In parallel, WBC from same patients are similarly analyzed to determine 
germline versus somatic mutations. The genomic alterations in prostate cancer specific 
genes will be confirmed by orthogonal molecular methods from RNA extracted from non- 
enriched blood samples collected in PAXgene tubes by an analytically validated 
orthogonal molecular method available in Clinical Chemistry at MSK.25 
 
The CTC blood samples will be drawn in kits provided for the study, will be labeled and 
delivered to the central laboratory at MSKCC, and the blood will be processed and 
analyzed as described in the Laboratory Manual (Appendix C: Circulating Tumor Cell 
(CTC) Laboratory Manual) outlining collection and analysis procedures for CTC (all done 
at MSKCC). 
 
10.9 
Whole Blood Lymphocyte Assay 
A blood sample will be collected at baseline and Day 8 of Cycle 1to determine target 
inhibition through lymphocyte analysis. 
 
10.10  Buffy Coat for Germline DNA 
A blood sample will be collected at baseline for isolation of buffy coat and germline 
sequencing. 
 
10.11  FDG and FDHT PET 
We propose to study both FDG and optional FDHT PET imaging at baseline, 4 weeks 
after treatment initiation and at the time of progression (end-of-treatment), and to 
correlate the changes with treatment response. For the purposes of this trial, optional 
FDHT PET imaging will be performed at MSKCC under a separate PET acquisition 
protocol (MSKCC protocol 00-095). Image Analysis: The linking of molecular images of 
lesions (on a lesion by lesion basis) to drug response profiles is an important concept. 
We can now assess all the lesions in the body using whole-body PET and monitor their 
activity over time using a data analysis tool, PET-VCAR (volume computer assisted 
reading), which Dr. Steve Larson’s group has co-developed with GE Healthcare 
Systems. This application runs from within a PACS-integrated Advantage Workstation 
and contains software to load and segment PET/CT image sets. The PET-VCAR allows 
for registration of post-therapy PET/CT scans based on co-registration of the 
corresponding whole-body CT image sets. This co-registration allows lesions to be 
matched, ie, identified and followed over time. In this way, important data on individual 
lesion response can be acquired. These measured data, obtained by metabolic FDG 
PET imaging and AR expression FDHT PET imaging, will be compared with the primary 
endpoint of PFS. 
 
11.0 
TOXICITIES/SIDE EFFECTS 
 
11.1 
Defining Adverse Events 
 
11.1.1 Adverse Event (AE) 
An AE is defined as any adverse event associated with the use of a drug in humans, 
whether or not considered drug related, including the following: 


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•  An adverse event occurring in the course of the use of the medication in professional 
practice: an adverse event occurring from medication overdose, whether accidental or 
intentional; 
•  An adverse event occurring from drug abuse/misuse 
•  An adverse event occurring from drug withdrawal 
•  Inadvertent or accidental exposure to a drug product 
 
 
•  Medication error; suspected transmission of any infectious agent via a drug product, 
unexpected therapeutic or clinical benefit from use of a drug product; and any patient 
or subject who becomes pregnant while on a drug product. 
 
 
Currently, 206 subjects have participated in phase 1 studies including 145 subjects in 
single agent studies INK128-001 and INK128-002 (N = 106 and N = 39, respectively); 
and 61 subjects in the paclitaxel combination study INK128-003. Toxicities have been 
mostly Grades 1 and 2, reversible, and manageable with supportive care and/or 
interruption or dose reduction of study drug. Commonly reported study drug-related AEs 
have included hyperglycemia, asthenia, fatigue, mucosal inflammation, decreased 
appetite, rash, nausea, vomiting, and diarrhea. This emerging safety profile is consistent 
with those of other TORC1/2 and PI3K pathway inhibitors. 
 
As of 2012, there are no FDA-approved TORC1/2 inhibitors. Rapamycin and rapalogs 
are TORC1 inhibitors with well-described toxicity profiles. Common toxicities include the 
following: immunosuppression with the potential to increase the risk of both nonserious 
and serious infections, and/or malignancies; mucositis, stomatitis, and mouth sores with 
a frequency from 41% to 78%; anorexia (approximately 30%), pneumonitis including 
interstitial lung disease (5%-36%); diarrhea (25%-56%); skin toxicity (48%-66%) which 
manifests typically as maculopapular or acneform rash, skin dryness, eczema, skin 
discoloration, and nail dystrophy; hyperlipidemia (hypercholesteremia and/or 
hypertriglyceridemia) with incidences from 8% to 44%; hyperglycemia (8%-22%); 
thrombocytopenia (10%-33%); anemia (27%-94%); leucopenia (27%-38%); hypokalemia 
(11%-21%); hypophosphatemia (15%-49%); hypertension (4%-7% in renal cancer 
subjects); elevated serum creatinine (37%-57%); elevated liver function tests (about 
20%); arthralgia (25%-30%); asthenia (about 30%); peripheral edema (24%-35%). 
Serious infections have included sepsis, opportunistic infections, and even death. An 
increase in the development of lymphomas is also a possibility because of the 
immunosuppression. 
 
Additionally, hypersensitivity reactions (18%), and fatal bowel perforation (1%) have 
been reported. Rapidly progressive, and sometimes fatal, acute renal failure not clearly 
related to renal cancer disease progression, abnormal wound healing, and increased 
risk of developing intracerebral bleeding (including fatal outcomes) in subjects with 
central nervous system (CNS) malignancies and/or receiving anticoagulation therapy 
have been reported in subjects receiving temsirolimus. The toxicities of rapamycin or 
rapalogs are typically reversible and infrequently serious. MLN0128 targets both TORC1 
and TORC2, and thus may prove to have a different risk/benefit profile from the 


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rapalogs. There is no human information available on inhibition of TORC2 alone. The 
safety profile of MLN0128 continues to be explored in advanced malignancies, including 
non-Hodgkin lymphoma (NHL), and hematologic malignancies. 
 
11.1.2 Unexpected Adverse Event 
An unexpected AE is any event not associated by nature or intensity with the 
Investigational agent under study. The Agent Specific Adverse Event List (ASAEL) 
contains events that are considered expected for expedited reporting purposes only. A 
listing of expected and unexpected events for the agents under investigation in this 
study may be found in the Investigator’s Brochure. 
 
11.1.3 Adverse Events of Special Interest 
Any newly identified malignancy or case of active pulmonary tuberculosis (TB) occurring 
after first administration of MLN0128 in subjects participating in this clinical study must 
be reported. These events are to be considered serious only if they meet the definition of 
an SAE. 
 
11.1.4 Serious Adverse Event (SAE) 
An SAE is defined as any untoward medical occurrence that at any dose: 
 
• 
Results in death. 
 
• 
Is life-threatening (refers to an AE in which the patient was at risk of death at the 
time of the event.  It does not refer to an event which hypothetically might have 
caused death if it were more severe). 
 
• 
Requires inpatient hospitalization or prolongation of an existing hospitalization 
(see clarification in the paragraph below on planned hospitalizations). 
 
• 
Results in persistent or significant disability or incapacity. (Disability is defined 
as a substantial disruption of a person’s ability to conduct normal life functions). 
 
• 
Is a congenital anomaly/birth defect. 
 
• 
Is a medically important event. 
 
This refers to an AE that may not result in death, be immediately life threatening, or 
require hospitalization, but may be considered serious when, based on appropriate 
medical judgment, may jeopardize the patient, require medical or surgical intervention to 
prevent 1 of the outcomes listed above, or involves suspected transmission via a 
medicinal product of an infectious agent.   Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, 
blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse; any organism, virus, or infectious 
particle (eg, prion protein transmitting Transmissible Spongiform Encephalopathy), 
pathogenic or nonpathogenic, is considered an infectious agent. 
 
Clarification should be made between a serious AE (SAE) and an AE that is considered 
severe in intensity (Grade 3 or 4), because the terms serious and severe are NOT 
synonymous.  The general term severe is often used to describe the intensity (severity) 


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of a specific event; the event itself, however, may be of relatively minor medical 
significance (such as a Grade 3 headache). This is NOT the same as serious, which is 
based on patient/event outcome or action criteria described above, and is usually 
associated with events that pose a threat to a patient’s life or ability to function.  A 
severe AE (Grade 3 or 4) does not necessarily need to be considered serious.  For 
example, a white blood cell count of 1000/mm3 to less than 2000 is considered Grade 3 
(severe) but may not be considered serious.  Seriousness (not intensity) serves as a 
guide for defining regulatory reporting obligations. 
 
11.2 
Recording Adverse Events 
 
11.2.1 Timeframe for Recording Adverse Events and Serious Adverse Events 
For each subject, AEs and SAEs occurring after informed consent is obtained  should be 
recorded until the subject has completed his participation in the study. 
 
An SAE must be reported if it occurs during a subject’s participation in the study 
(whether receiving study drug or not) and within 30 days of receiving the last dose of 
Study Product in a clinical trial, whichever is longer. 
 
Any SAE that is ongoing when a subject completes his participation in the Study must be 
followed until any of the following occurs: 
 
• 
The event resolves or stabilizes; 
• 
The event returns to baseline condition or value (if a baseline value is available); 
• 
The event can be attributed to agents(s) other than the Study Product, or to factors 
unrelated to Study conduct. 
 
Any subsequent AE felt to be possibly related to the use of the Study Product should be 
reported. 
 
11.2.2 Recording of Adverse Events and Serious Adverse Events 
 
 
 
Recording should be done in a concise manner using standard, acceptable medical 
terms. 
 
The AE recorded should not be a procedure or a clinical measurement (i.e., a laboratory 
value or vital sign) but should reflect the reason for the procedure or the diagnosis based 
on the abnormal measurement. 
 
Preexisting conditions that worsen in severity or frequency during the Study should also 
be recorded (a preexisting condition that does not worsen is not an AE). 
 
Further, a procedure or surgery is not an AE; rather, the event leading to the procedure 
or surgery is considered an AE. Any event requiring in-patient hospitalization that occurs 
during the course of a subject’s participation in a trial must be reported as an SAE. 
Surgeries or procedures planned prior to entry into the study for a pre-existing condition 
that has not worsened do not meet the criteria for SAE reporting. 


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If a clinical significant worsening from baseline is observed in any laboratory or other test 
parameter (e.g., ECG, angiogram), physical exam finding, or vital sign, a corresponding 
clinical AE should be recorded. 
 
If a specific medical diagnosis has been made, that diagnosis or syndrome should be 
recorded as the AE whenever possible. However, a complete description of the signs, 
symptoms and investigations which led to the diagnosis should be provided. For 
example, if clinically significant elevations of liver function tests are known to be 
secondary to hepatitis, “hepatitis” and not “elevated liver function tests” should be 
recorded. If the cause is not known, the abnormal test or finding should be recorded as 
an AE, using appropriate medical terminology (e.g., thrombocytopenia, peripheral 
edema, QT prolongation). 
 
11.3 
Grading Adverse Events 
 
11.3.1 Grading severity 
All AEs will be graded for intensity on a scale of 0 to 5. Severity grades will be recorded 
and based on the CTCAE v4.0. 
 
11.3.2 Attributing causality 
The investigator must evaluate all clinical AEs and clinically significant abnormal 
laboratory values for possible causal relationship to MLN0128. Causality attribution will 
be decided using the criteria outlined in Table . 
 
Table 14. Relationship of adverse event to study drug 
 
Relationship 
Description 
Unrelated 
AE is clearly not related to study drug 
Unlikely 
AE is doubtfully related to study drug 
Possible 
AE may be related to study drug 
Probable 
AE is likely related to study drug 
Definite 
AE is clearly related to study drug 
 
 
Abnormal laboratory values of clinical significance that were present at baseline and did 
not change in severity or frequency during experimental therapy or intervention and 
those that can obviously be attributed to underlying disease will be recorded as 
unrelated. 
 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
 
Response and progression will be evaluated in this study using a combination of the 
international criteria proposed by the Response Evaluation Criteria in Solid Tumors 
(RECIST) Committee and modified for prostate cancer 23, 24 and the guidelines for 
prostate cancer endpoints developed by the Prostate Cancer Clinical Trials Working 
Group (PCWG2).21 
 
Traditional measures of response reflect when a treatment is working and measures of 
progression indicate when a drug should be stopped. Because assessing response in 


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bone (the most common site of prostate cancer spread) is uncertain and the clinical 
significance of PSA changes in response to therapy is not a reliable predictor of 
response, measures of response have been expanded to include measures of 
progression.Patients will need to be reevaluated for response every 8 weeks or more 
frequently (if necessary) according to the guidelines above. 
 
13.0 
CRITERIA FOR REMOVAL FROM STUDY 
 
In the absence of treatment delays because of AEs, treatment will continue until one of 
the following criteria applies: 
 
• Patient decides to withdraw from the study 
• Disease progression 
 
o symptomatic disease progression at any time 
o objective clinical disease progression 
 
• Intercurrent illness that prevents further administration of treatment 
• Unacceptable AE(s) that may or may not be directly related to treatment but that, in the 
judgment of the treating physician, makes it dangerous for the patient to be retreated 
• General or specific changes in the patient’s condition that render the patient 
unacceptable for further treatment, in the judgment of the investigator 
 
Because an excessive rate of withdrawals can render the study uninterpretable, 
unnecessary withdrawal of patients should be avoided. When a patient discontinues 
treatment early, the investigator should make every effort to contact the patient and to 
perform a final evaluation. The reason(s) for withdrawal should be recorded. 
 
13.1 
Definition of Progression 
When evaluating tumors, the following definitions will apply: 
 
• 
Disease progression will be defined radiographically, by bone scan and CT scan, by 
at least one of the following: 
 
• 
Progression on bone scans with ≥ 2 new lesions not consistent with tumor 
flare, confirmed on a second bone scan ≥ 6 weeks later that shows ≥ 2 
additional new lesions. 
 
• 
Soft tissue disease progression by RECIST 1.1 criteria 
 
• 
Preclinical data have suggested that endocrine manipulations of prostate cancer 
cells may result in short-term changes in PSA mRNA expression and circulating PSA 
levels that do not necessarily reflect changes in tumor cell number. Instead, they 
represent a direct result of modulation of AR activity. Therefore, PSA is not a reliable 
marker of tumor response, especially when the treatment instituted involves 
endocrine manipulations. As a result, other, AR-independent, markers are needed. 
Consequently, for the purposes of this study, a rise in PSA will not be considered 
disease progression. In addition, PSA has not been shown to correlate with survival 
or progression for patients with metastatic castration-resistant prostate cancer and 
has not been used as a marker for disease progression in any of the phase 3 trials 


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resulting in approval of treatments such as abiraterone (de Bono et al., N Engl J 
Med, 2011), enzalutamide (Scher et al., N Engl J Med, 2012), or alpharadin (Parker 
et al,. N Engl J Med, 2013).  Accordingly, PSA will not be used as a marker of 
disease progression for this study. 
 
• 
CTC count will be monitored during the study, but a rise in CTC will not be part of the 
definition of disease progression. 
 
13.2 
Safety Evaluation 
Safety will be evaluated according to the NCI Common Terminology Criteria for Adverse 
Events (CTCAE) v4.0. Safety assessments will be based on medical review of AE 
reports and the results of vital sign measurements, physical examinations, and clinical 
laboratory tests throughout the conduct of the study. The incidence of AEs will be 
tabulated and reviewed for potential significance and clinical importance. 
 
14.0 
BIOSTATISTICS 
 
14.1 
Analysis Population 
The analysis population will include all subjects who receive at least 1 dose of study 
drug. 
 
14.2 
Demographics and Baseline Characteristics 
Demographic variables will include age, race, ethnicity, height, and weight. Baseline 
disease characteristics will include time from diagnosis, time from radical prostatectomy 
to PSA progression and time from radical prostatectomy to initiation of study drug. 
 
14.3 
Safety Analysis 
 
14.3.1 Adverse events 
Safety analysis will be summarized using the Safety Population defined as any patient 
receiving any part of study treatment. 
 
Extent of exposure to study treatment will be summarized and details will be provided. 
Treatment emergent AEs are those events that occur or worsen on or after first dose of 
study drug up through 30 days post last dose. AEs will be coded using the MedDRA 
coding system and all AEs will be graded according to the most current National Cancer 
Institute Common Terminology Criteria for Adverse Events (CTCAE). 
 
14.3.2 Clinical laboratory tests 
All Grade 3 and 4 abnormal laboratory test results will be reported according to the NCI- 
CTCAE Version 4.0 criteria. 
 
14.4 
Statistical Procedures 
The primary objective of this study is to determine the efficacy of MLN0128 in patients 
with metastatic castration-resistant prostate cancer. The primary endpoint of the study is 
six month progression free survival (6mPFS). A patient that is followed for six months 
and remains progression free during this time period is defined as a success. A patient 


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that is lost to follow-up prior to the six month landmark time is counted as a failure for the 
6mPFS endpoint. 
 
Recently there have been two phase III studies demonstrating an overall survival benefit 
for patients with CRPC. The 6mPFS endpoint has therefore been selected based on 
these single agent studies using the hormonal intervention abiraterone (6mPFS 44%) 
and chemotherapy cabazitaxel (6mPFS 23%).  In this study, a two-stage design that 
differentiates between 6mPFS rates of 0.30 and 0.50 will be used to assess treatment 
efficacy. In the first stage of the study 21 patients will be enrolled (Cohort 1). If at most 6 
patients remain alive and progression free at 6 months, accrual will be terminated. If at 
least 7 patients are alive and progression free at 6 months, an additional 21 patients will 
be accrued in this cohort (Cohort 2). At the conclusion of this second stage, if at least 
17/42 patients remain alive and progression free at 6 months, then the treatment will be 
declared sufficiently active. The probability of declaring the treatment effective is 0.10 
when the 6mPFS in the population is 0.30 and increases to 0.90 when the 6mPFS is 
0.50. It is anticipated that accrual in this trial will be completed in approximately 1-2 
years. 
 
Secondary Anti-tumor Endpoints 
 
PSA. Summary tables and waterfall plots describing change in PSA relative to baseline 
will be reported at 8 weeks (or earlier for those who discontinue therapy), and 
separately, the maximal change at any time on study will also be reported for each 
patient using summary tables and waterfall plots. 
 
Soft Tissue. Summary tables and waterfall plots describing change in target lesions 
relative to baseline will be reported every 8 weeks using RECIST version 1.1 (Response 
Criteria in Solid Tumors) criteria. Separately, the maximal change at any time on study 
will also be reported using summary tables and waterfall plots. 
 
Bone Disease. Summary tables describing the change in radionuclide bone scans 
relative to baseline will be reported every 8 weeks. Since there are no validated criteria 
for response on radionuclide bone scan, results will be recorded as “no new lesions” or 
“new lesions”. The appearance of ≥ 2 new lesions on confirmatory bone scan is 
considered disease progression. 
 
Exploratory Endpoints 
 
Circulating tumor cells, FDG PET imaging, and FDHT PET imaging will be recorded over 
time and their temporal association with progression-free survival time (and overall 
survival time) will be modeled using a time-dependent Cox model. 
 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION 
PROCEDURES 
 
15.1 
Research Participant Registration 
Confirm eligibility as defined in the section entitled Criteria for Patient/Subject Eligibility. 


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Obtain informed consent, by following procedures defined in section entitled Informed 
Consent Procedures. 
 
During the registration process registering individuals will be required to complete a 
protocol specific Eligibility Checklist. 
 
All participants must be registered through the Protocol Participant Registration (PPR) 
Office at Memorial Sloan-Kettering Cancer Center. PPR is available Monday through 
Friday from 8:30am – 5:30pm at 646-735-8000. Registrations must be submitted via the 
PPR Electronic Registration System (http://ppr/). The completed signature page of the 
written consent/RA or verbal script/RA, a completed Eligibility Checklist and other 
relevant documents must be uploaded via the PPR Electronic Registration System. 
 
15.2 
Randomization 
This study will not require randomization procedures. 
 
16.0 
DATA MANAGEMENT 
 
16.1 
Quality Assurance 
A Research Study Assistant (RSA) will be assigned to the study. The responsibilities of 
the RSA include project compliance, data collection, abstraction and entry, data 
reporting, regulatory monitoring, problem resolution and prioritization, and coordination 
of the activities of the protocol study team. 
 
16.2 
Data and Safety Monitoring 
 
16.2.1 Data Collection and Review 
Data for each subject will be recorded by authorized site personnel on eCRFs (an 
electronic case report form), which must be completed for every subject who signs an 
informed consent form. The eCRF will be signed by the Investigator to affirm the 
accuracy of information recorded. 
 
Data will be reviewed routinely by the Study Coordinator assigned at the study site and 
by the Data Management Department of the Sponsor (or designee) to assess missing 
data and inconsistencies. Accrual rates, extent and accuracy of evaluations, and follow- 
up will be monitored periodically throughout the study period; potential problems will be 
brought to the attention of the study team for discussion and action. The study team will 
conduct random audits of data quality and protocol compliance. 
 
The responsibilities of the Investigator include protocol compliance, problem resolution 
and prioritization, regulatory monitoring, and ensuring the accuracy, completeness, 
legibility, and timeliness of the data reported to the Sponsor on the case report form. The 
responsibilities of the Study Coordinator include data collection and entry on the case 
report form, verification, abstraction, and reporting; and coordination of activities of the 
study team. 
 
Direct access to source data and documents will be permitted for representatives of the 
Quality Assurance Department of the Sponsor (or designee), the Institutional Review 


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Board/Ethics Committee, and regulatory agencies. All information that may specifically 
identify the subject will be protected prior to provision of this access. 
 
 
16.2.2 Source documents 
Study personnel will record clinical data in each patient’s source documents (i.e., the 
patient’s medical record). Source documentation will be made available to support the 
patient research record. Study monitors will review entries on the CRFs at regular 
intervals, comparing the content with source documents. 
 
16.2.3 Record retention 
The investigator will maintain adequate and accurate records to enable the conduct of 
the study to be fully documented and the study data to be subsequently verified. After 
study closure, the investigator will maintain all source documents, study-related 
documents, and the CRFs. The original of all such Reports will be maintained by the 
Participating Member(s) until the later of:  (a) two (2) years following the date a New 
Drug Application is approved for the Study Drug that is the subject of the Clinical Trial; or 
(b) two (2) years after the Investigational New Drug Application for such Study Drug is 
terminated or withdrawn, or such longer period of time as may be required by 
Participating Member policies, applicable laws, rules or regulations. 
 
17.0 
PROTECTION OF HUMAN SUBJECTS 
 
17.1 
Privacy 
MSKCC’s Privacy Office may allow the use and disclosure of protected health 
information pursuant to a completed and signed Research Authorization form. The use 
and disclosure of protected health information will be limited to the individuals described 
in the Research Authorization form. A Research Authorization form must be completed 
by the Principal Investigator and approved by the IRB and Privacy Board (IRB/PB). 
 
It is also stated in the consent and Research Authorization that research data (e.g. 
genomic sequence) may be placed into databases monitored by the National Institutes 
of Health, and may be made accessible to investigators approved by the U.S. 
government. It is difficult to identify genotype/phenotype specifics at this time and 
therefore, the requirements for submission of genotype/phenotype data into the NIH 
GWAS Repository (or any other public database) will be followed as per the MSKCC IRB 
GWAS SOP-503. 
 
17.2 
Serious Adverse Event (SAE) Reporting 
 
17.2.1 Millennium Reporting timelines 
All SAEs, AEs of Special Interest, and Pregnancy/Paternal Exposure Reports should be 
reported to Millennium within 24-hours of becoming aware of the event(s). 
 
17.2.2 Millennium Procedures for Reporting Serious Adverse Events 
AEs may be spontaneously reported by the patient and/or in response to an open 
question from study personnel or revealed by observation, physical examination, or 


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other diagnostic procedures.  Any clinically relevant deterioration in laboratory 
assessments or other clinical finding is considered an AE. When possible, signs and 
symptoms indicating a common underlying pathology should be noted as one 
comprehensive event.  AEs which are serious must be reported to Millennium 
Pharmacovigilance (or designee) from the first dose of MLN0128 up to and including 30 
days after administration of the last dose of MLN0128.  Any SAE that occurs at any time 
after completion of MLN0128 treatment or after the designated follow-up period that the 
sponsor-investigator and/or sub-investigator considers to be related to any study drug 
must be reported to Millennium Pharmacovigilance (or designee).  Planned hospital 
admissions or surgical procedures for an illness or disease that existed before the 
patient was enrolled in the trial are not to be considered AEs unless the condition 
deteriorated in an unexpected manner during the trial (e.g., surgery was performed 
earlier or later than planned).  All SAEs should be monitored until they are resolved or 
are clearly determined to be due to a patient’s stable or chronic condition or intercurrent 
illness(es). 
 
Since this is an investigator-initiated study, the principal investigator Dr. Rathkopf, also 
referred to as the sponsor-investigator, is responsible for reporting serious adverse 
events (SAEs) to any regulatory agency and to the sponsor- investigator’s EC or IRB. 
Regardless of expectedness or causality, all SAEs must also be reported to Millennium 
Pharmacovigilance or designee as soon as possible, but no later than 24 hours of the 
sponsor-investigator’s observation or awareness of the event.  See below for contact 
information for the reporting of SAEs to Millennium Pharmacovigilance. 
 
The sponsor-investigator should fax the SAE Form within five calendar days after 
becoming aware of the event.  A sample of an SAE Form will be provided.  Follow-up 
information on the SAE may be requested by Millennium. The SAE report must include 
event term(s), serious criteria, and the sponsor-investigator’s or sub-investigator’s 
determination of both the intensity of the event(s) and the relationship of the event(s) to 
study drug administration.  Intensity for each SAE, including any lab abnormalities, will 
be determined by using the NCI CTCAE v. 4 as a guideline, whenever possible.  The 
criteria are available online at http://ctep.cancer.gov/reporting/ctc.html. 
 
Relationship to all study drugs for each SAE will be determined by the investigator or 
sub-investigator by responding yes or no to the question: Is there a reasonable 
possibility that the AE is associated with the study drug(s)? 
 
Sponsor-investigator must also provide Millennium Pharmacovigilance with a copy of all 
communications with applicable regulatory authorities related to the study or study 
drug(s), including, but not limited to, telephone conversation logs, as soon as possible 
but no later than 5 calendar days of such communication. 
 
SAE and Pregnancy Reporting Contact Information: 
 
Millennium Pharmacovigilance 
 
SAE and Pregnancy Reporting Contact Information 
 
Cognizant Contacts: 


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Fax:  1-800-963-6290 
 
Email: TakedaOncoCases@cognizant.com 
 
 
 
Suggested Reporting Form: 
 
• 
SAE Report Form (a sample will be provided) 
 
• 
US FDA MedWatch 3500A: 
http://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/default.htm 
 
• 
Any other form deemed appropriate by the sponsor-investigator 
 
Product Complaint Information: 
 
A product complaint is a verbal, written, or electronic expression that implies 
dissatisfaction regarding the identity, strength, purity, quality, or stability of a drug 
product.  Individuals who identify a potential product complaint situation should 
immediately contact MedComm Solutions (see below) and report the event. Whenever 
possible, the associated product should be maintained in accordance with the label 
instructions pending further guidance from a Millennium Quality representative. 
 
 
 
For Product Complaints, 
 
call MedComm Solutions at 
877-674-3784 (877 MPI DRUG) 
(US and International) 
  
 
Product complaints in and of themselves are not AEs.  If a product complaint results in 
an SAE, an SAE form should be completed and sent to PPD. 
 
17.2.3 Millennium Procedures for Reporting Drug Exposure During Pregnancy 
and Birth Events 
 
If a female partner of a male patient becomes pregnant during the male patient’s 
participation in this study, the sponsor-investigator must also immediately fax a 
completed Pregnancy Form to the Millennium Department of Pharmacovigilance or 
designee. Every effort should be made to follow the pregnancy for the final pregnancy 
outcome. 
 
Suggested Pregnancy Reporting Form: 
 
Pregnancy Report Form (a sample will be provided) 
 
The investigator must assess each event to determine if it meets the criteria for 
classification as a Serious Adverse Event (SAE). An SAE as defined in the Code of 
Federal Regulations (21CFR312.32) is any event that: 


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• 
Results in subject death 
 
• 
Is life-threatening 
 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
 
 
 
• 
Results in persistent or significant disability/incapacity (i.e., a substantial disruption 
in a person’s ability to conduct normal activities of daily living) 
• 
Is a congenital anomaly/birth defect. 
• 
Is a suspected transmission of infectious agents by a medicinal product 
 
In addition, an important medical event that may not result in death, be life-threatening, 
or require/prolong hospitalization may be considered an SAE when, based on 
appropriate medical judgment, it may jeopardize the subject and/or may require medical 
or surgical intervention to prevent one of the outcomes listed above. 
 
Examples of such events include allergic bronchospasm requiring intensive treatment in 
an emergency room or at home; blood dyscrasias or convulsions that do not result in 
inpatient hospitalization or the development of drug dependency or drug abuse. 
 
Progression of malignancy 
Progression of a patient’s malignancy should not be considered an AE, unless in the 
investigator’s opinion, study treatment resulted in an exacerbation of the patient’s 
condition. If disease progression results in death or hospitalization while on study or 
within 30 days of the last dose, progressive disease will be considered an SAE. 
 
Life-threatening events 
A life-threatening event is any AE that places the patient at immediate risk of death from 
the reaction as it occurs. It is not a reaction that, had it occurred in a more severe form, 
might have caused death. 
 
Hospitalization or prolongation of hospitalization 
Hospitalization encompasses any inpatient admission (even for less than 24 hours) 
resulting from a precipitating, treatment-emergent AE. For chronic or long-term patients, 
inpatient admission also includes transfer within the hospital to an acute or intensive 
care inpatient unit. Hospitalizations for administrative reasons or a non-worsening 
preexisting condition should not be considered AEs (e.g., admission for workup of a 
persistent pretreatment laboratory abnormality, yearly physical exam, protocol-specified 
admission, elective surgery). Pre-planned treatments or surgical procedures should be 
noted in the baseline documentation. Hospitalization because of an unplanned event will 
be deemed an SAE. 
 
Prolongation of hospitalization is any extension of an inpatient hospitalization beyond the 
stay anticipated or required for the original reason for admission. 
 
Significant disability 
Disability is a substantial disruption of the patient’s ability to conduct normal life 
functions. 


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Congenital anomaly 
If the female partner of a male patient becomes pregnant during the course of the study, 
the treating physician must be notified immediately. All pregnancies will be followed until 
resolution (i.e., voluntary or spontaneous termination or birth) and assessed for 
congenital anomalies and birth defects. 
 
Medical significance 
An event that is not fatal or life-threatening and that does not necessitate hospitalization 
may be considered serious if, in the opinion of the investigator, it jeopardizes the 
patient’s status and might lead to medical or surgical intervention to prevent any of the 
above outcomes. Such medically significant events could include allergic bronchospasm 
requiring intensive treatment in the emergency room or at home, blood dyscrasias that 
do not result in inpatient hospitalization, or the development of drug dependency or 
abuse. 
 
17.2.4 MSKCC Procedures for Reporting Serious Adverse Events 
Any SAE must be reported to the IRB/PB as soon as possible but no later than 5 
calendar days. The IRB/PB requires a Clinical Research Database (CRDB) SAE report 
be submitted electronically to the SAE Office at sae@mskcc.org. The report should 
contain the following information: 
 
Fields populated from CRDB: 
 
• 
Subject’s name (generate the report with only initials if it will be sent outside of 
MSKCC) 
• 
Medical record number 
• 
Disease/histology (if applicable) 
• 
Protocol number and title 
 
Data needing to be entered: 
 
• 
The date the adverse event occurred 
• 
The adverse event 
• 
Relationship of the adverse event to the treatment (drug, device, or intervention) 
• 
If the AE was expected 
• 
The severity of the AE 
• 
The intervention 
• 
Detailed text that includes the following 
o A explanation of how the AE was handled 
o A description of the subject’s condition 
o Indication if the subject remains on the study 
o If an amendment will need to be made to the protocol and/or consent 
form. 
 
The PI’s signature and the date it was signed are required on the completed report. 


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For IND/IDE protocols: 
The CRDB AE report should be completed as above and the FDA assigned IND/IDE 
number written at the top of the report. If appropriate, the report will be forwarded to the 
FDA by the SAE staff through the IND Office. 
 
 
 
Sponsor-investigator must also provide Millennium Pharmacovigilance with a copy of all 
communications with applicable regulatory authorities related to the study or study 
drug(s), including, but not limited to, telephone conversation logs, as soon as possible 
but no later than 5 calendar days of such communication. 
 
17.2.5 Adverse events 
Safety analysis will be summarized using the Safety Population defined as any patient 
receiving any part of study treatment. 
 
Extent of exposure to study treatment will be summarized and details will be provided. 
Treatment emergent AEs are those events that occur or worsen on or after first dose of 
study drug up through 30 days post last dose. AEs will be coded using the MedDRA 
coding system and all AEs will be graded according to the most current National Cancer 
Institute Common Terminology Criteria for Adverse Events (CTCAE). 
 
17.2.6 Clinical laboratory tests 
All Grade 3 and 4 abnormal laboratory test results will be reported according to the NCI- 
CTCAE Version 4.0 criteria. 
 
18.0 
INFORMED CONSENT PROCEDURES 
 
Before protocol-specified procedures are carried out, consenting professionals will 
explain full details of the protocol and study procedures as well as the risks involved to 
participants prior to their inclusion in the study. Participants will also be informed that 
they are free to withdraw from the study at any time. All participants must sign an 
IRB/PB-approved consent form indicating their consent to participate. This consent form 
meets the requirements of the Code of Federal Regulations and the Institutional Review 
Board/Privacy Board of this Center. The consent form will include the following: 
 
1.  The nature and objectives, potential risks and benefits of the intended study. 
2.  The length of study and the likely follow-up required. 
3.  Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of 
supportive care for therapeutic studies.) 
4.  The name of the investigator(s) responsible for the protocol. 
5.  The right of the participant to accept or refuse study interventions/interactions 
and to withdraw from participation at any time. 
 
Before any protocol-specific procedures can be carried out, the consenting professional 
will fully explain the aspects of patient privacy concerning research specific information. 


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In addition to signing the IRB Informed Consent, all patients must agree to the Research 
Authorization component of the informed consent form. 
 
Each participant and consenting professional will sign the consent form. The participant 
must receive a copy of the signed informed consent form. 


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19.0 
REFERENCES 
 
1.  Taylor BS, Schultz N, Hieronymus H, et al. Integrative genomic profiling of human prostate 
cancer. Cancer Cell 2010;18:11-22. 
2.  George DJ, Armstrong AJ, Creel P, et al. A phase II study of RAD001 in men with hormone- 
refractory metastatic prostate cancer (HRPC). 2008 ASCO Genitourinary Cancers 
Symposium; February 14-16, 2008; San Francisco, California;Abstract 181. 
3.  Rathkopf DE, Danila DC, Chudow JJ, et al. Anti-insulin-like growth factor-1 receptor (IGF-IR) 
monoclonal antibody cixutumumab plus mammalian target of rapamycin (mTOR) inhibitor 
temsirolimus in metastatic castration-resistant prostate cancer (CRPC). 2010 ASCO Annual 
Meeting; June 4-8, 2010; Chicago, IL;Abstract TPS242. 
4.  Rathkopf DE, Danila DC, Morris MJ, et al. Anti-insulin-like growth factor-1 receptor (IGF-1R) 
monoclonal antibody cixutumumab (cix) plus mTOR inhibitor temsirolimus (tem) in metastatic 
castration-resistant prostate cancer (mCRPC): Results of a phase I pilot study. 2011 ASCO 
Annual Meeting; June 3-7, 2011; Chicago, IL;Abstract e15081. 
5.  Guertin DA, Stevens DM, Saitoh M, et al. mTOR complex 2 is required for the development 
of prostate cancer induced by Pten loss in mice. Cancer Cell 2009;15:148-59. 
6.  Carver BS, Chapinski C, Wongvipat J, et al. Reciprocal feedback regulation of PI3K and 
androgen receptor signaling in PTEN-deficient prostate cancer. Cancer Cell 2011;19:575-86. 
7.  Nardella C, Carracedo A, Alimonti A, et al. Differential requirement of mTOR in postmitotic 
tissues and tumorigenesis. Sci Signal 2009;2:ra2. 
8.  O'Reilly KE, Rojo F, She QB, et al. mTOR inhibition induces upstream receptor tyrosine 
kinase signaling and activates Akt. Cancer Res 2006;66:1500-8. 
9.  Jemal A, Siegel R, Xu J, et al. Cancer statistics, 2010. CA Cancer J Clin 2010;60:277-300. 
10. Scher HI, Heller G. Clinical states in prostate cancer: toward a dynamic model of disease 
progression. Urology 2000;55:323-7. 
11. Chiang GG, Abraham RT. Targeting the mTOR signaling network in cancer. Trends in 
Molecular Medicine 2007;13(10):433-42. 
12. Sabatini DM. mTOR and cancer: insights into a complex relationship. Nature Reviews. 
Cancer 2006;6(9):729-34. 
13. Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, et al. Efficacy of 
everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo controlled 
phase III trial. Lancet 2008;372(9637):449-56. 
14. Fasolo A, Sessa C. Current and future directions in mammalian target of rapamycin inhibitors 
development. Expert Opinion on Investigational Drugs 2011;20(3):381-94. 
15. Benjamin D, Colombi M, Moroni C, Hall MN. Rapamycin passes the torch: a new generation 
of mTOR inhibitors. Nature Reviews. Drug Discovery 2011;10(11):868-80. 
16. Sankhala K, Mita A, Kelly K, Mahalingam D, Giles F, Mita M. The emerging safety profile of 
mTOR inhibitors, a novel class of anticancer agents. Targeted Oncology 2009;4(2):135-42. 
17. RAPAMUNE (sirolimus) Oral Solution and Tablets [package insert]. Philadelphia, PA: Pfizer; 
2010. 
18.  AFINITOR (everolimus) tablets for oral administration [package insert]. East Hanover, NJ: 
Novartis; 2011. 
19. TORISEL Kit (temsirolimus) injection, for intravenous infusion only [package insert]. 
Philadelphia, PA: Wyeth Pharmaceuticals Inc (Pfizer); 2011. 
20.Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228-47. 
21.Scher HI, Halabi S, Tannock I, et al. Design and end points of clinical trials for patients with 
progressive prostate cancer and castrate levels of testosterone: recommendations of the 
Prostate Cancer Clinical Trials Working Group. J Clin Oncol 2008;26:1148-59. 


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22. Danila DC, Fleisher M, Scher HI. Circulating tumor cells as biomarkers in prostate cancer. 
Clin Cancer Res 2011;17:3903-12. 
23. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to 
treatment in solid tumors. European Organization for Research and Treatment of Cancer, 
National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl 
Cancer Inst 2000;92:205-16. 
24. Scher HI, Morris MJ, Kelly WK, et al. Prostate cancer clinical trial end points: "RECIST"ing a 
step backwards. Clin Cancer Res 2005;11:5223-32. 
25. Danila DC, Anand A, Schultz N, et al. Analytic and clinical validation of a prostate cancer- 
enhanced messenger RNA detection assay in whole blood as a prognostic biomarker for 
survival. Euro Urology 2013. 


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20.0 
APPENDICES 
 
Appendix A: Performance Status Criteria 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Description 
% 
Description 
0 
Normal activity. Fully active, able to 
continue all predisease 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 (eg, 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 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 
> 50% of waking hours. 
40 
Disabled, requires special care and 
assistance 
30 
Severely disabled, hospitalization indicated. 
Death not imminent. 
4 
100% bedridden. Completely disabled, 
cannot carry on any self-care, totally 
confined to bed or chair. 
20 
Very sick, hospitalization indicated. Death 
not imminent. 
10 
Moribund, fatal processes progressing 
rapidly 
5 
Dead 
0 
Dead 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Appendix B: Study Calendar 
 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
and 4 
Subsequent 
cycles 
Assessments
1 
Within 
30 days 
prior to 
initiation 
of 
protocol 
therapy 
Within 
14 days 
prior to 
initiation 
of 
protocol 
therapy 
C1 
D1 
C1 
D8 
C1 
D15 
C1 
D22 
C2 D1 
C2 
D8 
C2 
D15 
C2 
D22 
D1 
D15 
D1 
Every 
8 
Weeks 
End of Treatment 
(Within 28 days of 
last dose of study 
medication) 
Informed consent 
X 
Medical history, 
demographics 
X 
Interim medical history, 
Physical Exam
2
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology & 
Chemistry
3
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coag, PT, PTT, INR 
X 
X 
X 
X 
X 
HbA1c 
X 
X 
C3D1 
C6 & q3 
cycles 
Serum Testosterone 
X 
PSA 
X 
X 
X 
X 
X 
X 
Blood for CTC studies 
X 
X 
X 
X 
X 
X 
Whole blood 
lymphocyte
4
 
X 
X 
Buffy coat for germline 
DNA 
X 
Daily Fasting glucose
5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
ECG
6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECHO/MUGA 
X 
Contrast enhanced (if 
feasible) CT & 
Radionuclide bone 
scan 
X 
C3D1 
X
7 
X
8 
FDG PET scans
9 
X 
X 
X 
Optional FDHT PET 
scans
10 
X 
X 
X 
Optional tumor biopsy
11 
X 
X 
X 
Treatment 
administration 
X---------------------------------------------------------------------------------------------------------------------------------------X 
AE assessment 
X------------------------------------------------------------------------------------------------------------------------------------------------------------------X 
Concomitant 
medications 
X--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------X 


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1With the exception of ECGs, assessments may be done within 24-48 hours of dosing with MLN0128 administration 
2PE symptom directed post D1. Physical examination includes vital signs, HEENT (head, eyes, ears, nose, and throat), chest, cardiac, abdominal, extremities, neurologic, 
and lymph node examinations. Weight will be recorded at every visit. Height will be recorded at screening visit only. KPS will be recorded at every visit. Vital signs incl ude 
upright blood pressure, heart rate, respiratory rate, and oral or aural body temperature. 
3Fasting, including electrolytes and lipid profile 
4Whole blood lymphocytes will be collected 0 to 1hr post treatment with MLN0128 on MLN0128 treatment days. 
5Daily at home with glucometers for first 6 months then twice weekly. If applicable, if changes to metformin dose, resume daily monitoring 
6C1D1 ECG pre dose, 2 hr post dose and 4 h post dose (+/- 15 minutes); C2D1 ECG pre dose and 2 h post dose (+/- 15 minutes); all other ECGs 2 h post dose (+/- 15 
minutes) 
7CT and bone scan can be performed ± 7 days during treatment period. 
8CT and bone scan can be performed ± 7 days at the time of progression, unless performed in the 30 days prior. 
9FDG PET scans are performed at baseline, week 4 (±7 days) and progression (within 28 days of last dose). Baseline and End of treatment PET scans will be performed 
with contrast (if feasible). 
10Optional FDHT PET (patients on protocol 00-095) are performed at baseline, week 4 (±7 days) and progression (within 28 days of last dose). 
11Biopsies are optional but requested of all patients. Biopsy is done at baseline, 4 weeks (±7 days) and at the time of progression when feasible (within 28 days of last 
dose). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Appendix C: Circulating Tumor Cell (CTC) Laboratory Manual 
 
 
1.  BACKGROUND 
 
A critical area of unmet medical need in prostate cancer management is the development of 
tumor specific markers to select targeted therapies and to reliably assess patient clinical 
outcome.  Changes  in  PSA  associate  poorly  with  survival  post  therapy,  and  conventional 
imaging is limited in the assessment of distant metastases. We and others have demonstrated 
that it is feasible to isolate and characterize circulating tumor cells (CTCs) from a blood sample 
in real time. CTC number has been proposed as a marker of prognosis pre-therapy and as a 
surrogate for treatment efficacy post-therapy in phase III clinical trials powered to detect a 
difference in survival with treatment. In addition, we have shown that a significant proportion of 
patients with CRPC have genomic amplification of the androgen receptor (AR) gene, or an 
increased AR gene copy number. 
 
The measurement of CTC number is performed with a semiautomated system, CellSearch 
(Veridex), which uses an EpCAM (epithelial common antigen molecule) antibody-based 
immunomagnetic antibody-capture technology. The approach combines an enriching step from 
blood of epithelial cells with an EpCAM antibody conjugated to immunomagnetic beads, and a 
negative selection by differentiating CTCs from CD45-expressing cells in order to reduce the 
mononuclear cell fraction. 
 
In addition to providing pre-treatment prognostic and post-treatment efficacy information, the 
isolated CTCs can be evaluated at the DNA, RNA, and protein level for the expression of 
specific biological determinants. Current methodology using immunomagnetic isolation as well 
as FACS sorting has allowed MSKCC to develop assays to study specific molecular profiles in 
enriched CTC specimens. 
 
Patients will be drawn for correlative studies related to CTC at the following time-points: 
Screening, Day 1 of each cycle, and at the end of treatment (time of treatment discontinuation). 
Specimens are to be collected using kits provided for the study, and shipped same day to 
MSKCC. A +/-2 day window around each time point is allowed if necessary for scheduling 
patient visits. CTC blood samples should not be drawn on Fridays. 
 
The collection of blood is summarized below: 
 
Circulating Tumor 
Cell Sampling 
Screening 
Day 1 of 
each cycle 
End of Treatment 
(time of treatment 
discontinuation) 
CellSave (2 tubes) 
X 
X 
X 
EDTA (1 tube) 
X 
X 
X 
PAXgene (2 tubes) 
X 
X 
X 


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2.  DESCRIPTION OF COLLECTION TUBES 
 
 
 
CellSave tube: Evacuated blood collection 
tube containing a proprietary fixative for the 
preservation of CTCs. 
 
 
 
 
 
EDTA tube: Evacuated blood collection tube 
for plasma collection and genotyping analysis. 
  
 
 
 
 
 
 
PAXgene tube: Evacuated blood collection tube 
containing a proprietary reagent which stabilizes RNA 
integrity for gene expression analyses. 
 
 
 
 
3.  COLLECTION OF BLOOD SAMPLES 
 
At each time point, blood samples will be drawn in the following order: 2 Cell Save tubes, EDTA 
tube, and 2 PAXgene tubes last. Samples will then be processed as described below, labeled, 
and shipped to MSKCC Chemical Chemistry on the same day of collection. All samples must be 
kept at room temperature. 
 
CellSave Tube (for CTC Collection) 
In each tube, 7.5 ml of peripheral blood will be collected. It is essential that the tubes are filled 
completely in order to be processed for CTC analysis. After collection, the tube must be inverted 
eight times to prevent clotting and then can be stored at room temperature until same day 
shipment. 
 
EDTA Tube (for CTC Collection) 
Ten mL of peripheral blood will be collected in a lavender top tube provided in the drawing kits. 
It is essential that the tube is filled completely in order to collect enough genetic material for 
analysis. 
 
PAXgene Tubes (for mRNA Collection) 
In each tube, 2.5 ml of peripheral blood will be collected. The tubes will be held below the 
patient’s arm. After collection of the blood, invert the tube 8 to 10 times and ship same day. It is 
essential that the tubes are filled completely in order to be processed for mRNA extractions. 


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4.    LABELING AND TRANSPORTING OF BLOOD SAMPLES 
 
Patient  identification  must  be  anonymous.  Submitted  documents  and samples  will  have  a 
unique anonymous identifier for each patient, consisting of a study identifier derived from the 
study-sponsor’s database. This identifier will be used for the purposes of the study only, and will 
be distinct from the patient identification (medical record) number used at each site. 
 
The blood samples must be shipped on the day of collection to the MSKCC Clinical Chemistry 
Laboratory for processing, using the shipping boxes that will be provided. Fill out the CTC 
requisition form completely, which will be included in the kit provided. Include the original 
requisition form in the shipment to MSKCC. Retain the copy for your records. 
 
Samples should be kept at room temperature at all times. Shipping reservations must be 
made to allow delivery within 24 hr of specimen collection, and prior to 2:00 PM the next day. If 
at all feasible, CTC samples should not be drawn on a Friday. A +/-2 day window around 
each time point is allowed if necessary for scheduling patient visits around this restriction. 
 
The shipping labels should be addressed to: 
MSKCC Clinical Chemistry Laboratory 
Memorial Hospital, Schwartz 359 
Rashmi Kamath 
Attn. CTC samples for MLN0128 
1275 York Avenue 
New York, NY 10065 
tel (212) 639-5969 
  
5.  PROCESSING AND ANALYSIS OF BLOOD SAMPLES 
 
Samples received at the reference MSKCC Clinical Chemistry laboratory will be processed for 
CTC enumeration and profiling studies. Upon arrival at the laboratory, personnel will ensure that 
the minimum volume of blood has been collected for these studies. 
 
CTC Enumeration and Interpretation 
 
Blood collected in CellSave tubes will be processed on the CellTracks AutoPrep System with 
the CellSearch Circulating Tumor Cell Kit which is intended for the enumeration of CTCs of 
epithelial origin (CD45-, EpCAM+, and cytokeratins 8+, 18+, and/or 19+) in whole blood. 
 
The methodology involves semiautomatic immunomagnetic selection of CTCs based on capture 
with an anti-EpCAM antibody and immunofluorescence analysis. In short, samples drawn in 
CellSave tubes containing cell preservatives, maintained at room temperature and shipped to 
MSKCC, will be processed on the CellSearch Epithelial Cell system (Veridex) after EpCAM 
antibody-covered ferroparticles are added and incubated at room temperature. A magnetic field 
is used to collect cells of interest without centrifugation. After unbound supernatant has been 
removed, the enriched samples are processed for nucleic acid staining with DAPI (4',6- 
diamidino-2-phenylindole),   for   markers   for   epithelial   cells   with   anti-cytokeratin   CK-PE. 
Leukocytes are excluded with an anti-CD45 immunofluorescent antibody. Stained cells are 


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analyzed on a fluorescence microscope using the CellTrack Analyzer II and CTCs are defined 
as cytokeratin positive, DAPI nucleated cells lacking CD45 markers. Automatically selected 
images are reviewed by the operator for identification of tumor cells. Androgen receptor (AR) 
protein analysis employing a fluorescein conjugate antiandrogen receptor antibody may be 
tested in order to explore the overexpression of AR in CTCs, and (if performed) will be scored 
based on the number of cells expressing AR relative to the total number of CTCs. Quality 
control  will  be  maintained  using  standard  procedures.  Using  CellSearch  technology  for 
metastatic prostate cancer, a value of ≥ 5 CTCs (per 7.5 ml tube) is considered abnormal, with ≥ 
50 being the suggested minimum for molecular profiling studies. 
 
Molecular Profiling of CTC 
 
Genomic DNA: Flow cytometry has yielded CTC events almost 100 times as high as those 
from  CellSearch,  but  more  importantly has  increased  the  proportion  of  patients  with  CTC 
number sufficient for profiling. Blood collected in the second CellSave tube would be processed 
for CTC enrichment by FACS sorting. 
 
Mononucleated cells are obtained through Ficoll-Hypaque density gradient centrifugation and 
then double-stained with EpCAM-PE antibody to identify CTC, and with CD45-APC antibody to 
identify white blood cells; DAPI staining is used to exclude dead cells. EpCAM-positive cells are 
counted and isolated using FACS on MoFlo cell sorter (DAKO), with the exclusion of cells that 
are CD45 and DAPI positive. The EpCAM positive cells are sorted by FACS in parallel with 
CD45 positive WBC, deposited in sequential wells in equal quantity onto plates that are stored 
at -80C for batch processing. These cells will be used to obtain genomic DNA for whole genome 
amplification (WGA). 
 
Whole genome amplification (WGA) will be performed, followed by quality control PCR, and 
direct sequencing for AR and other relevant mutations. Sequencing results will be analyzed in 
comparison to the known AR mutations and available SNP data, and any AR mutations found in 
CTC will be confirmed in a second sample. Identified AR mutations in CTC will be compared to 
AR sequencing in WBC obtained from same patients to differentiate somatic mutations from 
germline SNPs. In addition to AR gene, we propose to sequence other highly relevant genes for 
prostate cancer previously described or identified in our Oncogenomics project. 
 
Gene Analysis: Isolation of mRNA from CTC enriched by flow cytometry will also be performed 
from blood drawn into EDTA anticoagulant blood tubes at baseline and with treatment. Primer 
directed reverse transcription will be performed immediately, and samples can be frozen and 
stored for gene analysis in batches. Expression of prostate-specific mRNAs, such as AR, PSA 
(KLK3), and KLK2, as well as for fusion genes specific to prostate cancer, such as TMPRSS- 
ERG, will be tested in CTC. 
 
Point mutations or prostate cancer specific gene products will be confirmed by PCR from RNA 
extracted from non-enriched blood samples collected in PAXgene tubes. This will allow us to 
determine the limits of detection based on the presence of contaminating normal cells, 
considering the dilution effects of non-malignant mononuclear cell populations on a prostate- 
specific as opposed to prostate cancer specific gene or gene mutation. 


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Protein    Analysis:    Peripheral    blood    mononuclear    cells    (PBMC)    obtained    through 
Ficoll-Hypaque density gradient centrifugation may also be stained and plated onto glass slides 
for the purpose of immunocytochemistry for AR protein expression and cellular localization in 
CTC before and after treatment. 
 
 
 
Appendix D: Glossary of Abbreviations and Acronyms 
 
ADR 
adverse drug reaction 
ADT 
androgen-deprivation therapy 
AE 
adverse event 
AI 
accumulation index 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
ANOVA 
analysis of variance 
APTT 
activated partial thromboplastin time 
AR 
androgen receptor 
ASAEL 
Agent Specific Adverse Event List 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration-time curve 
AUC(INF) 
area under the concentration-time curve from time zero extrapolated to infinite 
time 
AUC(0-T) 
area under the concentration-time curve from time zero to the time of the last 
quantifiable concentration 
AUC(TAU) 
area under the concentration-time curve in one dosing interval 
AUMC(INF) 
area under the moment concentration time curve extrapolated to infinity 
A-V 
atrioventricular 
β-HCG 
beta-human chorionic gonadotrophin 
BMI 
body mass index 
BP 
blood pressure 
BSA 
Body Surface Area 
BUN 
blood urea nitrogen 
Ca++ 
calcium 
CBC 
complete blood count 


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CFR 
Code of Federal Regulations 
 
CI 
confidence interval 
 
Cl- 
chloride 
 
Clcr 
creatinine clearance 
CLNR 
nonrenal clearance 
CLR 
renal clearance 
CLT 
total body clearance 
 
Cmax 
maximum plasma concentration 
Cmin 
trough observed concentration 
CNS 
central nervous system 
CRF 
case report form 
 
CRPC 
castration resistant prostate cancer 
 
CT 
computerized tomography 
 
CTC 
circulating tumor cell 
 
CTCAE 
Common Terminology Criteria for Adverse Events 
 
DEV 
deviation from the nominal value 
 
DHEA 
dehydroepiandrosterone 
 
DHEA-S 
dehydroepiandrosterone sulfate 
 
DHT 
dihydrotestosterone 
DLT 
dose-limiting toxicity 
ECG 
electrocardiogram 
EEG 
electroencephalogram 
EORTC 
European Organisation for Research and Treatment of Cancer 
 
FDA 
Food and Drug Administration 
 
FDG-PET 
2-[18F]fluoro-2-deoxyglucose positron emitting tomography 
 
FDHT 
18-fluoro-dehydrotestosterone 
 
GnRH 
gonadotropin-releasing hormone 
 
HIPAA 
Health Insurance Portability and Accountability Act 
 
HIV 
human immunodeficiency virus 
 
HR 
heart rate 


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ICH 
International Conference on Harmonisation 
 
IEC 
Independent Ethics Committee 
 
IHC 
immunochemical 
 
IND 
investigational new drug 
IRB 
Institutional Review Board 
ITT 
intent-to-treat population 
IV 
intravenous 
K+ 
potassium 
 
K3EDTA 
potassium ethylenediaminetetraacetic acid 
 
KLK1 
kallikrein 1 
 
LD 
longest diameter 
 
LDH 
lactate dehydrogenase 
 
MAD 
maximum administered dose 
 
MRI 
magnetic resonance imaging 
 
MSKCC 
Memorial Sloan-Kettering Cancer Center 
 
MTD 
maximum tolerated dose 
 
N 
number of subjects or observations 
 
NCI 
National Cancer Institute 
 
NIH 
National Institutes of Health 
 
NSAID 
nonsteroidal anti-inflammatory drug 
 
PCCTC 
Prostate Cancer Clinical Trials Consortium 
 
PCRP 
Department of Defense Prostate Cancer Research Program 
 
PD 
progressive disease 
 
PET 
positron emission tomography 
 
PFS 
progression-free survival 
 
PI 
principal investigator 
 
PK 
pharmacokinetics 
 
PSA 
prostate-specific antigen 
 
PSADT 
prostate-specific antigen doubling time 
 
PT 
prothrombin time 


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PTT 
partial thromboplastin time 
 
RBC 
red blood cell 
 
RECIST 
Response Evaluation Criteria in Solid Tumors 
 
SUV 
standardized uptake value 
t 
temperature 
t1/2 
terminal half-life 
 
T 
time 
 
TAUC(TAU) 
trapezoidal area under the concentration-time curve in one dosing interval 
 
TAUC(0-T) 
trapezoidal area under the concentration-time curve from time zero to the time of 
the last quantifiable concentration 
 
TDP 
time to disease progression 
 
TGP 
prostate-specific transglutaminase 
 
Tmax 
time of maximum observed concentration 
Vss 
volume of distribution at steady-state 
WBC 
white blood cell 


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MLN0128 
DAY 
DATE 
Time 
MLN0128 
taken: 
# of 
MLN0128 
tablets 
taken: 
If dose not taken or if full dose not taken, 
please provide an explanation: 
Example 01/01/12 
9:00 AM 
1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
Appendix E: Pill Diary 
 
 
Pill Diary for Protocol #13-143 
  
 
 
Patient ID Number:  
 
Bottle or Lot#:  
_ 
 
Number of Pills Given:  
_ 
Pill Bottle(s) returned:  Circle Yes or No 
 
Total Daily Dose:   
_ 
Number of Pills returned:   
 
 
(To be completed by RN) 
 
PLEASE FILL OUT AND BRING THIS SHEET AT YOUR NEXT VISIT. 
 
SPECIAL INSTRUCTIONS for MLN0128: Take the 4mg daily dose by mouth in the 
morning at approximately the same time each day. It is recommended that you 
take your dose after a light meal and with 8 ounces of water. DO NOT make up 
vomited doses. 
 
CYCLE #:   
 
 
# of WEEKS:  
 


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12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
 
 
Patient Signature:   
 
Date:   
 
 
Physician/Research RN Signature:   
 Date:   
 
 
Physician/Research RN Comments:  
 


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Appendix F: Glucose Monitoring Diary 
Glucose Monitoring Diary for Protocol #13-143 
 
Patient ID Number:  
 
 
SPECIAL INSTRUCTIONS for MLN0128 Glucose Monitoring: You must have your 
glucose level checked first thing in the morning before eating anything and the 
result will be written in the space provided in this diary. If your Doctor requires 
additional testing, the results must also be recorded. 
 
CYCLE #:   
 
# of WEEKS:   
_ 
 
DAY 
DATE 
Blood Glucose Time: 
Blood 
Glucose 
Result: 
Are 
additional 
blood 
glucose 
results 
indicated 
below? 
(circle Y/N) 
Example 
01/01/12 
9:00 
AM 
Y/N 
1 
AM 
Y/N 
2 
AM 
Y/N 
3 
AM 
Y/N 
4 
AM 
Y/N 
5 
AM 
Y/N 
6 
AM 
Y/N 
7 
AM 
Y/N 
8 
AM 
Y/N 
9 
AM 
Y/N 
10 
AM 
Y/N 
11 
AM 
Y/N 
12 
AM 
Y/N 
13 
AM 
Y/N 
14 
AM 
Y/N 
15 
AM 
Y/N 


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16 
AM 
Y/N 
17 
AM 
Y/N 
18 
AM 
Y/N 
19 
AM 
Y/N 
20 
AM 
Y/N 
21 
AM 
Y/N 
22 
AM 
Y/N 
23 
AM 
Y/N 
24 
AM 
Y/N 
25 
AM 
Y/N 
26 
AM 
Y/N 
27 
AM 
Y/N 
28 
AM 
Y/N 
29 
AM 
Y/N 
30 
AM 
Y/N 
 
 
Additional blood glucose results (if needed): 
 
Date 
Time 
Result 
Date 
Time 
Result 
Date 
Time 
Result 
 
 
Patient Signature:   
 
Date:   
 
 
Physician/Research RN Signature:   
 Date:   
 
 
Physician/Research RN Comments:  
 


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Appendix G: New York Heart Association Classification of Cardiac Disease 
 
 
Class 
Functional Capacity 
Objective Assessment 
I 
Patients with cardiac disease but without resulting 
limitations of physical activity. Ordinary physical 
activity does not cause undue fatigue, palpitation, 
dyspnea, or anginal pain. 
No objective evidence of 
cardiovascular disease. 
II 
Patients with cardiac disease resulting in slight 
limitation of physical activity. They are comfortable 
at rest. Ordinary physical activity results in fatigue, 
palpitation, dyspnea, or anginal pain. 
Objective evidence of 
minimal cardiovascular 
disease. 
III 
Patients with cardiac disease resulting in marked 
limitation of physical activity. They are comfortable 
at rest. Less than ordinary activity causes fatigue, 
palpitation, dyspnea, or anginal pain. 
Objective evidence of 
moderately severe 
cardiovascular disease. 
IV 
Patients with cardiac disease resulting in inability to 
carry on any physical activity without discomfort. 
Symptoms of heart failure or the anginal syndrome 
may be present even at rest. If any physical activity 
is undertaken, discomfort is increased. 
Objective evidence of 
severe cardiovascular 
disease. 
Source: The Criteria Committee of New York Heart Association. Nomenclature and Criteria 
for Diagnosis of Diseases of the Heart and Great Vessels. 9th Ed. Boston, MA: Little, Brown 
& Co; 1994:253-256. 


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Appendix H: Strong Inhibitors and Inducers of CYP2C9, CPY2C19, and CYP3A4
 
 
 
Strong Inhibitors 
Strong Inducers 
Indinavir 
Carbamazepine 
Nelfinavir 
Phenobarbital 
Ritonavir 
Phenytoin 
Clarithromycin 
Rifabutin 
Itraconazole 
St. John’s wort 
Ketoconazole 
Troglitazone 
Nefazodone 
Secobarbital 
Fluconazole 
Rifampin 
Telithromycin 
 
Fluvoxamine 
 
Mibefradil 
 
Omeprazole 
 
Ticlopidine 
 
Fruit and juice: 
 
Star fruit 
 
Pomegranate 
 
Grapefruit 
 
Seville oranges 
 
Papaya 
 
Source: http://www.ganfyd.org/index.php?title=Inhibitors_of_CYP3A4 and 
http://medicine.iupui.edu/clinpharm/ddis/