Clinical trial NCT02514824
Conditions: Merkel Cell Carcinoma
Keywords: recurrent merkel cell carcinoma metastatic merkel cell carcinoma
Sponsor: Dana-Farber Cancer Institute
Start date: 2015-10-01; Completion date: 2017-06-01
Enrollment: 9 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This research study is studying a targeted therapy as a possible treatment for merkel cell carcinoma.

\- The name of the study intervention involved in this study is: MLN0128.

Detailed description:
This is a phase I/II clinical trial. A phase I clinical trial tests the safety of an investigational intervention and also tries to define the appropriate dose of the investigational intervention to use for further studies. "Investigational" means that the intervention is being studied.

The FDA (the U.S. Food and Drug Administration) has not approved MLN0128 as a treatment for any disease.

MLN0128 may prevent tumor cells from dividing and growing by selectively and potently inhibiting a chemical, mTOR kinase, which regulates cell growth and survival.

Patients with merkel cell carcinoma have been observed to sometimes carry genetic alterations in their tumor cells which may make the cancer more sensitive to inhibition by MLN0128. In this research study,the investigators are studying the usefulness of MLN0128 in merkel cell carcinoma cases.

Arms: arm 1: Phase 1 dose level 1 participants receive MLN01283 3 mg orally once daily of a 28 day cycle.

Participants are treated indefinitely until disease progression, unacceptable toxicity or withdrawal for other reasons. arm 2: Phase 1 dose level 2 participants receive MLN01283 4 mg orally once daily of a 28 day cycle.

Participants are treated indefinitely until disease progression, unacceptable toxicity or withdrawal for other reasons. arm 3: Phase 1 dose level 3 participants receive MLN01283 5 mg orally once daily of a 28 day cycle.

Participants are treated indefinitely until disease progression, unacceptable toxicity or withdrawal for other reasons. arm 4: Phase 2 participants receive MLN01283 at the recommended phase 2 dose (RP2D) orally once daily of a 28 day cycle.

Participants are treated indefinitely until disease progression, unacceptable toxicity or withdrawal for other reasons.
Interventions: intervention 1: MLN0128
Intervention descriptions: intervention 1: Investigational mTOR kinase inhibitor

Protocol documents:
Prot_000.pdf: 
 
 
 
 
FRONT SHEET: 
MLN0128 FOR METASTATIC MERKEL CELL CARCINOMA 
NCT02514824 
IRB Approval Date: Amendment 4/March 18, 2016 


 
 
 
 
 
 
DF/HCC Protocol #: 15-223 
TITLE: MLN0128 in recurrent/metastatic merkel cell carcinoma 
Principal Investigator (PI):  
  
Guilherme Rabinowits, MD  
Dana Farber Cancer Institute 
450 Brookline Avenue Boston, MA 02215 
guilherme_rabinowits@dfci.harvard.edu  
Sub-Investigators (DFCI): 
Robert Haddad, MD  
Jochen Lorch, MD  
Nicole Chau, MD  
Peter Hammerman, MD, PhD 
James DeCaprio, MD 
Manisha Thakuria, MD  
IND #: 126536 
Protocol Type / Version # / Version Date: Amendment 4/March 18, 2016  
Agent: MLN0128  
i  


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SCHEMA OF THE STUDY 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
1. 
OBJECTIVES  
1.1 
Study Design ............................................................................................................4 
1.2 
Primary Objectives...................................................................................................4 
1.3 
Secondary Objectives...............................................................................................4 
2. 
BACKGROUND .................................................................................................................4 
2.1 
Study Disease...........................................................................................................4 
2.2 
IND Agent................................................................................................................5 
2.3 
Nonclinical Summary ..............................................................................................6 
2.4 
Summary of Effects in Humans in Advanced Solid Malignancies and  
Hematologic Malignancies ......................................................................................8 
2.5 
Rationale ................................................................................................................16 
2.6 
Correlative Studies Background ............................................................................17 
3. 
UPDATED MANUFACTURING PROCESS...................................................................18  
4. 
CLINICAL SUMMARY OF SAFETY..............................................................................18  
4.1 
Special Warnings and Precautions for Use.............................................................18  
4.2 
Interactions with Other Medications and Other Forms of Interactions .................19  
5. 
PARTICIPANT SELECTION...........................................................................................20 
5.1 
Inclusion Criteria ...................................................................................................20 
5.2 
Exclusion Criteria ..................................................................................................21 
 
5.3  
Inclusion of Women and Minorities ......................................................................22 
6. 
REGISTRATION PROCEDURES ...................................................................................22 
6.1 
General Guidelines for DF/HCC and DF/PCC Institutions ...................................22 
6.2 
Registration Process for DF/HCC and DF/PCC Institutions.................................23 
7. 
TREATMENT PLAN........................................................................................................23 
7.1 
Treatment Regimen................................................................................................23 
7.2 
Pre-Treatment Criteria ...........................................................................................24 
7.3 
Agent Administration.............................................................................................24 
7.4 
General Concomitant Medication and Supportive Care Guidelines ......................28 
7.5 
Criteria for Taking a Participant Off Protocol Therapy.........................................28 
7.6 
Duration of Follow Up ...........................................................................................29 
7.7 
Criteria for Taking a Participant Off Study ...........................................................29 
8. 
DOSING DELAYS/DOSE MODIFICATIONS ...............................................................29 
8.1 
Management of Clinical Events.............................................................................30 
8.2 
Excluded Concomitant Medications and Procedures ............................................38 


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8.3 
Permitted Concomitant Medications and Procedures ............................................39 
8.4 
Precautions and Restrictions ..................................................................................39 
9. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS............................40 
9.1 
Expected Toxicities................................................................................................40 
9.2 
Adverse Event Characteristics...............................................................................41 
9.3 
Routine Adverse Event Reporting .........................................................................42 
10. 
PHARMACEUTICAL INFORMATION..........................................................................43 
10.1 
MLN0128...............................................................................................................43 
11. 
BIOMARKER STUDIES..................................................................................................46 
12. 
STUDY CALENDAR .......................................................................................................47 
13. 
MEASUREMENT OF EFFECT........................................................................................50 
13.1 
Antitumor Effect – Solid Tumors ..........................................................................50 
14. 
DATA REPORTING / REGULATORY REQUIREMENTS ...........................................57 
14.1 
Data Reporting .......................................................................................................57 
14.2 
Data Safety Monitoring..........................................................................................57 
15. 
STATISTICAL CONSIDERATIONS...............................................................................57 
15.1 
Study Design/Endpoints.........................................................................................57 
15.2 
Sample Size, Accrual Rate and Study Duration ....................................................58 
16. 
PUBLICATION PLAN .....................................................................................................59 
17. 
ADMINISTRATIVE REQUIREMENTS………………..................................................59 
17.1 
Product Complaints………………………............................................................59 
18. 
REFERENCES ..................................................................................................................59 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ..................................................61 
APPENDIX B 
INFORMATION ON POSSIBLE DRUG INTERACTIONS...................64 
 
 


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1. 
OBJECTIVES 
1.1 
Study Design 
This is a single arm, non-randomized, phase I/II, pilot/feasibility study, to determine the 
recommended phase II dose (RP2D) and toxicity and efficacy of MLN0128 in metastatic/recurrent 
Merkel Cell Carcinoma (MCC), an orphan disease. Between 6 and 34 patients could be entered 
into this trial, a maximum of 18 in the phase I and a maximum of 16 in the phase II portion of the 
trial. The phase I design will be standard 3+3. The starting dose will be 3 mg QD. Each cohort will 
be evaluated for tolerability after completing 1 cycle of treatment before proceeding to escalation 
(4 mg QD or 5 mg QD) or de-escalation (2 mg QD or 2mg 5 days a week). Escalation/de-escalation 
w i l l not proceed beyond 5 mg QD or below 2 mg 5 days a week respectively. The phase II portion 
of the study will be conducted according to a two-stage phase II design. The phase II part of the 
study will use the RP2D determined during the phase I part of the study. 
1.2 
Primary Objectives 
Phase I: To determine the recommended phase II dose (RP2D)  
Phase II: To evaluate response rate (ORR) 
1.3 
Secondary Objectives 
To evaluate overall survival (OS) 
To evaluate progression-free survival (PFS)   
To evaluate safety/adverse events 
Identification of biomarkers predictive of response to therapy with MLN0128  
2. 
BACKGROUND 
2.1 
Study Disease 
Although uncommon, Merkel Cell Carcinoma (MCC) incidence has tripled in US from 1986 to 
2001.  It is an orphan and devastating disease, usually affecting elderly patients.  No standard of 
care is available for patients with recurrent or metastatic disease.  Given histologic and biologic 
similarities between MCC and Small Cell Lung Cancer, platinum/etoposide combination therapy 
is commonly used.  Although response rates can be as high as 60%, median duration of response 
is 8 months (less than 3 months for those with partial response) [1].  Response rates to second and 
third line therapies are substantially lower (40% and 20%, respectively), with most patients dying 
within a year with metastatic disease.  In addition, toxic death rate from chemotherapy for this 
patient population has been described as 4-8% [1].  


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More recently, a human polyomavirus (MCV) was implicated in the pathogenesis of MCC. It is 
constituted by 5,387 base pairs, encoding for the large T (LT) antigen and small T (ST) antigen, 
which act differently and sinergistically to promote cell proliferation and transformation. 
Shuda et al. [2] showed that MCV ST antigen reduced turnover of hyperphosphorylated 4E-BP1, 
which in turn increased eIF4E activity. Expression of a constitutively active 4E-BP1 that cannot 
be phosphorylated reversed MCV ST–induced cell transformation, which showed that the 
proliferative effects of MCV ST are caused by targeting downstream components of the AktmTOR 
pathway. These findings indicate that MCV ST targets cap-dependent translation though a 
mechanism that contributes to Merkel cell tumorigenesis. 
Lin et al. [3], using tissue microarray and immunohistochemistry, found that mTOR pathway was 
activated as indicated by positive staining of phosphorylation-4E-BP1, phosphorylation-S6K, and 
phosphorylation-mTOR regardless of MCV status. Two primary human MCC cell lines from two 
patients with lymph node metastases were established, demonstrating mTOR pathway 
upregulation and decreased autophagy in both MCC cells. Inhibition of mTOR pathway decreased 
cell proliferation and induced autophagy and cell death in MCC cells. Furthermore, cell death 
induced by mTOR inhibitors was independent of caspase activation and attenuated by an 
autophagy inhibitor, suggesting a rationale for potential new therapeutic targets.  
Finally, Nardi et al. [4] retrospectively profiled 60 primary MCC samples using a SNaPshot-based 
tumor genotyping assay to screen for common mutations in 13 cancer genes. Six of 60 were found 
to have PIK3CA gene activating mutations. Sanger sequencing of the primary MCC tumors 
detected one additional PIK3CA mutation (R19K) that had not been previously described in 
cancer. MCV was detected in 38 (66%) MCC cases. With one exception, the presence of MCV 
and activating mutations in PIK3CA appeared mutually exclusive. We observed that signaling 
through the PI3K/pAKT pathway was active in one MCV-positive and in all MCV-negative MCC 
cell lines, as evidenced by AKT phosphorylation.   
Based on the above data, we propose a phase I/II study evaluating the activity of MLN0128 in 
patients with metastatic/recurrent MCC. 
2.2 
IND Agent 
Millennium has developed MLN0128, which is a novel, highly selective, orally bioavailable 
adenosine 5’ triphosphate (ATP)-competitive inhibitor of the serine/threonine kinase referred to as 
the mechanistic target of rapamycin (mTOR). MLN0128 (formerly INK128) targets 2 distinct 
multiprotein complexes, mTORC1 and mTORC2. MLN0128 is being developed for both oncology 
and non-oncology indications. In oncology, MLN0128 is being investigated as a treatment for 
advanced solid tumors and hematologic malignancies, either as monotherapy or in combination 
with chemotherapy, other molecularly targeted therapies, or antihormonal agents. Non-oncology 
indications being investigated include fibrotic and inflammatory diseases in the lung or bronchioles 
such as idiopathic pulmonary fibrosis (IPF) and bronchiolitis obliterans syndrome (BOS). 
MLN0128 is also being developed in combination with MLN1117 (an oral phosphoinositide-3
nonhematologic 


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malignancies; information regarding this novel combination is provided to relevant investigators 
in the MLN0128 + MLN117 Investigator’s Brochure (IB). 
MLN0128 selectively and potently inhibits mTOR kinase (IC50 = 1.1 nM), inhibits mTORC1/2 
signaling, and prevents cellular proliferation. 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 [5]. mTORC1 is best known as a key regulator of protein translation through 
phosphorylation of 4EBP1 (the eukaryotic translation Initiation Factor 4E-binding Protein 1) and 
ribosomal protein S6 (known as S6) kinase. mTORC2 is best known for its ability to fully activate 
protein kinase B (AKT) by phosphorylation on the S473 site, which regulates proliferation and 
survival pathways [6].  
The mTOR complex (mTORC) is an important therapeutic target that is generally stable (ie, low 
tendency to 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 in the treatment of a number of indications including solid tumor and hematological 
malignancies, as either monotherapy or in combination with other chemotherapeutic agents. Like 
rapamycin, several newly approved rapalogs (temsirolimus and everolimus) are specific and 
allosteric inhibitors of mTORC1, and only partially inhibit mTORC1 signaling pathways. They do 
not directly inhibit mTORC2, which has shown to be an emerging target in cancer research. 
MLN0128 was developed to address the incomplete inhibition of the mTOR pathway by rapalogs. 
2.3 
Nonclinical Summary 
2.3.1 
Pharmacology  
MLN0128 selectively and potently inhibits mTOR kinase (the concentration inhibiting 50% of 
enzyme activity [IC50] is 1.1 nM), inhibits mTORC1/2 signaling, and prevents cellular 
proliferation.  
MLN0128 inhibited phosphorylation of downstream modulators of mTORC1and mTORC2 in 
human U87 glioblastoma tumor xenograft models in mice and showed strong tumor growth 
inhibition (TGI) at tolerable oral (PO) doses in all 8 xenograft models tested. 
2.3.2 
Safety Pharmacology  
MLN0128 has a low potential to affect the human ether-à-go-go related gene (hERG) potassium 
ion channel and did not affect cardiovascular (CV) parameters in vivo in telemeterized monkeys.  
2.3.3 
Drug Metabolism and Pharmacokinetics 


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MLN0128 was rapidly absorbed after PO administration to mice, rats, dogs, and monkeys, with 
high oral bioavailability. [14C]MLN0128 was rapidly and widely distributed throughout the body 
in Long-Evans rats; radioactivity was eliminated from most tissues at 48 hours postdose.  
MLN0128 displayed dose-proportional plasma exposures, a moderate propensity to cross the 
blood-brain barrier, and was modestly bound (70.5%) to human plasma proteins. MLN0128 
distributed mainly to the plasma of human blood. There was no obvious concentration-dependent 
red blood cell (RBC) distribution of MLN0128 in human blood.  
MLN0128 did not inhibit P-glycoprotein, but did inhibit breast cancer-resistance protein (BCRP), 
organic cation transporter (OCT)1 and (OCT)2.  
M1, the single metabolite (monohydroxylation product) observed in human microsomal 
incubations, was also observed in rats and monkeys. The main isozymes responsible for phase 1 
metabolism appear to be cytochrome P450 (CYP) 2C9, 2C19, and 3A4. MLN0128 did not induce 
CYP1A2, 2B6, and 3A4 activity and expression at concentrations up to 10 µM. MLN0128 
displayed low potential for inhibition and is not a time-dependent inhibitor of CYP1A2, 2B6, 2C8, 
2C9, 2C19, 2D6, and 3A4/5.  
Oral administration of MLN0128 in humans has a low potential for metabolic and transporterbased 
drug-drug interactions (DDIs), especially given clinical exposures observed to date after 
administration of the highest anticipated therapeutic dose to be used in the clinic in oncology 
indications (total maximum plasma concentration [Cmax] of 0.48 µM [free Cmax of 0.14 µM] at 
30 mg once weekly [QW]).  
2.3.4 
Toxicology  
The toxicologic profiles obtained in the Good Laboratory Practice (GLP)-compliant and non-
GLPcompliant studies in rats and monkeys were generally consistent with pharmacologic 
inhibition of mTORC1/2 activity.  Observed toxicities were mostly consistent between sexes. 
MLN0128 repeatdose GLP studies include completed 28-day and preliminary 3-month toxicology 
studies in rat and monkeys, and embryo-fetal studies in rats and rabbits. 
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. In addition to the previously mentioned effects, a single monkey in the 3-month 
toxicology study demonstrated a DLT of skin toxicity characterized as progressive acanthosis. The 
highest exposures tolerated in the preliminary 3-month rat and monkey toxicology studies were 
1233 and 194 nghr/mL, respectively. 
Adverse effects in rats included body weight loss, decreased activity, increased glucose and insulin 
levels, alterations in white blood cells, bone marrow and lymphoid depletion, thymic necrosis, 
oligospermia, 
testes 
degeneration/atrophy, 
nonglandular 
stomach 
epithelial 
degeneration/ulceration/hyperplasia, pancreatic islet degeneration and fibrosis, lens fiber 
degeneration with cataract correlate, adrenal cortex hypertrophy, pituitary atrophy secondary to 


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body weight loss, liver hepatocellular vacuolation, retinal dysplasia with or without optic nerve 
atrophy, and alveolar histiocytosis. The alveolar histiocytosis was only present in the 28-day rat 
study and was absent in the 3-month rat study. Both retinal dysplasia and alveolar histiocytosis are 
thought to be potential background findings. The pancreatic islet degeneration and fibrosis, as well 
as the other findings of lens fiber degeneration, pituitary atrophy, and liver vacuolation, were 
consistent with the mechanism of action (MOA) and effects observed with other rapalogs. The 
microscopic findings observed in the testes, epididymides, and eyes in the 28-day and/or 3-month 
rat studies were not resolved after a 14-day recovery period, while partial to complete resolution 
was seen in the lungs, thymus, nonglandular stomach, 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; skin 
ulceration/epidermal hyperplasia; acanthosis and hyperkeratosis; and adipose tissue depletion. 
Additionally, there were sporadic inflammatory findings among some animals that were of 
uncertain association to the test article. 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.  
Rat and rabbit range-finding embryo-fetal studies demonstrated teratogenic, fetotoxic, and 
abortive effects with MLN0128. Embryo-fetal lethality and/or teratogenic effects have been 
reported with the mTORC1 inhibitors rapamycin and the rapalogs. 
MLN0128 was negative for genotoxicity in an in vitro bacterial mutagenesis (Ames) assay, an in 
vivo rat micronucleus assay, and an in vivo rat comet assay. An in vitro chromosomal aberration 
assay with MLN0128 in human peripheral blood lymphocytes (PBLs) was positive for 
chromosomal aberrations in the presence and absence of metabolic activation.  
However, the weight of evidence from the combined results of a negative mutagenicity assay and 
negative genotoxicity assessments in 2 in vivo assays in 3 tissues (bone marrow, liver, and 
duodenum) demonstrate that MLN0128 does not present a genotoxic risk.  
MLN0128 was negative for phototoxicity in the 3T3 fibroblast assay.  
2.4 
Summary of Effects in Humans in Advanced Solid Malignancies and Hematologic 
Malignancies  


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MLN0128 is in clinical development as a single agent in 3 phase 1 studies including study INK128-
01 in patients with advanced solid malignancies, study INK128-002 in patients with multiple 
myeloma [MM], non-Hodgkin lymphoma [NHL] and Waldenström macroglobulinemia [WM]) 
and study C31002 to measure the effect of MLN0128 on QTc interval in patients with advanced 
solid malignancies.  It is also being investigated in combination with paclitaxel (with or without 
trastuzumab) in patients with advanced solid tumors (Ph1 study INK128-003), and in combination 
with exemestane or fulvestrant in women with ER+/HER2  (estrogen receptorpositive /human 
epidermal growth factor receptor 2 protein-negative) advanced or metastatic breast cancer (Ph1b/2 
study C31001)  
MLN0128 dosing regimens tested thus far include QD, QW, QD×3days per week (once daily for 
3 consecutive days followed by a 4-day dosing holiday every week), and QD×5days per week 
(once daily for 5 consecutive days followed by a 2-day dosing holiday every week). 
Please note that the data described in this section was obtained with the original unmilled 
MLN0128 active pharmaceutical ingredient (API); current manufacturing process produces milled 
MLN0128 API. 
2.4.1 
Safety and Efficacy in Oncology Studies  
In the clinical development plan, the safety and tolerability profile of single-agent MLN0128 is 
being studied in an ongoing phase 1, first-in-human, dose-finding study in patients with advanced 
solid malignancies (Study INK128-001) and in a completed phase 1 study (Study INK128-002) in 
patients with MM and WM. A third study (INK128-003) is being conducted in patients with solid 
tumors to evaluate the preliminary safety and efficacy of the combination of MLN0128 with 
paclitaxel, with or without trastuzumab. 
 1 dose of 
study drug across studies. A total of 18 deaths that occurred within 30 days of the last study drug 
dose had been reported to the clinical database as of the data cutoff; of these events, 1 (cardiac 
arrest; Study INK128-001) was considered related to MLN0128 (see section 5.3.1.1 of the IB Ed  
8)  
At least 1 treatment-emergent SAE, regardless of causality, had been reported in 125/335 patients 
(37%). Across the studies and regardless of causality or dosing regimen, the most common TEAEs 
included nausea, fatigue, hyperglycemia, vomiting, diarrhea, stomatitis, and decreased appetite. 
2.4.2 
Study INK128-001  
Study INK128-001 is a phase 1, first-in-human, dose-escalation study of single-agent MLN0128 
administered to patients diagnosed with advanced solid malignancies, including, but not limited 
to, colorectal, renal, endometrial, and urothelial tumors. Four dosing schedules are being evaluated 
(QD, QW, QD × 3d QW, and QD × 5d QW). Each schedule is administered in 28-day cycles. 


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As of 09 December 2014, a total of 194 patients had been enrolled. Median age at baseline was  
60 years (range, 24-89 years), most (95%) patients are white, and 54% are women. As of data 
 dose of MLN0128 in 2 treatment cycles, while 8% had entered 3 
cycles, and 10% had entered 4 cycles. The highest number of cycles that had been initiated as of 
data cutoff was 46.   
The maximum tolerated doses (MTDs) for the 4 schedules investigated in INK128-001 were 
determined to be 6 mg for QD dosing, 16 mg for QD × 3d QW dosing, 10 mg for QD × 5d QW 
dosing, and 40 mg for QW dosing.  
As of 09 December 2014, a total of 7 patients in this study had died within 30 days of their last 
dose of study drug as reported to the clinical database. One death was due to ventricular fibrillation 
and cardiac arrest, 1 was due to pleural effusion, 1 was due to sepsis, 1 was due to respiratory 
failure, and the remainder was due to disease progression. The event of ventricular fibrillation and 
cardiac arrest was the only case considered study drug-related; details are provided in section 
5.3.1.1. of the IB Ed8.  
As of the clinical database cutoff date, treatment-emergent SAEs had been reported for  
82 
 patients, overall) preferred 
terms were stomatitis in 7 patients (4%), pneumonia in 6 patients (3%), abdominal pain or 
anemia in 5, each (3%), and vomiting, asthenia, or renal failure acute in 4, each (2%).   
 
commonly reported TEAEs were nausea or hyperglycemia, which were each reported in 125 
patients (64%). The second most common TEAE was vomiting (54% of patients), followed by 
fatigue (51%).   
3 had been reported for 68% of 
treated  
3 TEAEs, regardless of causality, 
that  
s as of the data cutoff were hyperglycemia (14% of patients),  
fatigue or hypophosphatemia (8% each), asthenia (7%), anemia or stomatitis (6% each), and 
lymphopenia or nausea (5% of patients each).  
Of the 194 patients treated in Study INK128-001 as of the clinical data cutoff, 110 (57%) 
discontinued because of disease progression, 20 (10%) withdrew consent, and 15 (8%) were lost 
to follow-up or discontinued for other reasons.   
A total of 68 AEs led to study discontinuation among 35 patients (18%). Of these events,  
32 (47%), including 16 nonserious AEs, were reported as severity Grade 3, and 6 SAEs were Grade 
5. No Grade 4 events were reported as resulting in study discontinuation. Most (71%) events were 
considered study drug-related and had resolved as of the data cutoff date. 


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A total of 12 preferred terms were reported as leading to discontinuation for >1 patient, including 
rash (9 patients, including the terms maculopapular [5 patients], rash [2], and rash erythematous 
or rash pruritic [1 each]), nausea or stomatitis (7 patients each), pruritus or pruritus generalized (4 
patients total), and asthenia, fatigue, renal failure/renal failure acute (3 patients, each). Events 
reported in 2 patients included hyperglycemia, pain or pain in extremity, performance status 
decreased, and vomiting.   
2.4.3 
Study INK128-002  
Study INK-002 is a completed phase 1, open-label, dose-escalation study of oral MLN0128 
administered as a single agent in patients with relapsed or refractory hematologic malignancies 
(MM or non-Hodgkin lymphoma, including WM). A total of 39 patients received MLN0128 in 1 
of 2 regimens: 26 patients received QD doses (range, 2-7 mg) and 13 patients were dosed on a QD 
× 3d QW schedule (range, 9-12 mg). The MTD for the QD schedule was 4 mg. The MTD for the 
QD × 3d QW schedule was 9 mg.  
A total of 21 of the patients (54%) in this study were male and 87% were white. The median age 
at baseline was 61 years (range, 46-85 years). 
Two patients died during Study INK128-002. One death was due to a subdural hemorrhage, and 
the other was due to disease progression. Both events were considered by the investigator to be 
unrelated to MLN0128.  
Details of the subdural hemorrhage case, taken from the Final Clinical Study Report INK128-002, 
are as follows:  
 
Treatment-emergent SAEs were reported in Study INK128-002 for 11 patients (28%). No SAE 
occurred in more than 1 patient. Overall, most SAEs were considered severity Grade 2 or 3. Grade 
4 SAEs were reported in 2 patients: hyperviscosity syndrome and hyponatremia were reported in 


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1 patient in the 2-mg QD dose group (both events resolved); and acute renal failure was reported 
in 1 patient in the 12-mg QD × 3d QW dose group (resolved with sequelae).  
No SAEs were considered to be related to MLN0128 treatment, with the exception of 3 events that 
were reported in 1 patient. This patient experienced Grade 2 pneumonia on Day 58 that resolved 
without sequelae on Day 60. On Day 121, the same patient experienced SAEs of pneumonia (Grade 
2) and hypoxia (Grade 3). The 3 events improved by Day 125 and were resolved as of Day 142. 
All 3 events were considered by the investigator to be related to MLN0128.  
All patients in Study INK128-002 experienced at least 1 TEAE. Overall, nausea was the most 
frequently reported preferred term (in 56% of patients), followed by fatigue (49%), hyperglycemia 
(38%), thrombocytopenia (36%), and diarrhea (28%).  
 
Overall, a total of 20 patients (51%) in Study INK128-002 discontinued due to progressive disease, 
11 patients (28%) withdrew consent, and 6 (15%) discontinued due to investigator decision or 
other reasons.  
Most events leading to study discontinuation were considered nonserious. Fatigue was reported 
as resulting in study discontinuation in 2 patients; all other events were reported as leading to 
study discontinuation in 1 patient only.  
The DLTs taken from the Final Clinical Study Report INK128-002 are as follows: 
Dose-Limiting Toxicities during Cycle 1 – QD Schedule (Dose-escalation Evaluable Population) 
Preferred term 
MLN012 
8 
2 mg QD 
n = 3 
MLN012 
8 
4 mg QD 
n = 6 
MLN012 
8 
6 mg QD 
n = 6 
MLN012 
8 
7 mg QD 
n = 4 
Total 
QD  Dosing 
N = 19 
Patients  
with  Cycle  
1  
DLT(s) 
0 
1 
3 
1 
5 
Blood  
creatinine  
increased 
0 
0 
1 
0 
1 
Fatigue 
0 
0 
1 
0 
1 
Nausea 
0 
0 
1 
0 
1 
Stomatitis 
0 
1 
0 
0 
1 
Urticaria 
0 
0 
0 
1 
1 


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Vomiting 
0 
0 
1 
0 
1 
Source: Table 14.3.4. 
Abbreviations: AE = adverse event; DLT = dose-limiting toxicity; QD = once daily. 
At each level of summation (overall and preferred term), patients reporting > 1 AE were counted 
only once. 
Dose-Limiting Toxicities during Cycle 1 – QD × 3d QW Schedule (Doseescalation 
Evaluable Population) 
 
 
MLN0128 
MLN0128 
Total 
9 mg QD × 3d 12 mg QD × 3d QD × 3d  
 
QW 
QW 
QW 
Preferred term 
n = 6 
n = 7 
N = 13 
 
Patients with Cycle 1  
DLT(s) 
1 
3 
4
Asthenia 
0 
1 
1
Fatigue 
Mucosal  
1 
0 
1
inflammation 
0 
1 
1
Rash erythematous 
1 
0 
1
Thrombocytopenia 
0 
1 
1
 
Source: Table 14.3.4. 
Abbreviations: AE = adverse event; d = day(s); DLT = dose-limiting toxicity; QD 
= once daily; QW = each week. 
At each level of summation (overall and preferred term), patients reporting > 1 AE 
were counted only once. 
2.4.4 
Study INK128-003  
Study INK128-003 is a phase 1, open-label, dose-escalation study of oral MLN0128 
administered in 4-week cycles in combination with paclitaxel in patients with advanced solid 
malignancies (lung, ovarian, endometrial, breast, pancreatic, prostate, etc). As of the clinical data 
cutoff date, the treatment period for the primary endpoint had completed and long-term treatment 
for 1 patient remained ongoing. 
 study drug dose under 1 of 3 dosing schedules: QW; QD × 
3d QW; and QD × 5d QW. With each regimen, paclitaxel 80 mg/m2 is dosed on Days 1, 8, and 
15 of each cycle. Patients who test positive for the human epidermal growth factor receptor 2 
protein (HER2+) receive the combination and also receive trastuzumab (8 mg QW). 


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A total of 57% of the treated patients are female, and 93% are white. At baseline, the median age 
was 60 years (range 21-81 years). 
On the basis of dose escalation data, 8 mg of MLN0128 on the QD × 3d QW schedule was selected 
for the dose expansion phase in breast cancer patients. The QD × 5d QW and QW schedules were 
abandoned before MTDs were declared, as they were viewed as less convenient relative to the QD 
× 3d QW schedule from the perspective of administering the paclitaxel and trastuzumab 
combination.   
Overall in the dose expansion phase, patients entered a median of 3.0 treatment cycles (range, 1-
19 cycles) and a mean (SD) of 5.6 (6.07) cycles. The overall median duration of exposure was 7.5 
weeks, with a duration over 2-fold greater (11.1 weeks) in the MLN0128 8 mg QD×3days per 
week HER2- treatment group relative to the MLN0128 8 mg QD×3days per week HER2+ plus 
trastuzumab group (5.2 weeks). The median cumulative dose was 189.0 mg. Across treatment 
groups, patients received approximately 75% of their planned dose of MLN0128. 
As of the clinical data cutoff date, 10 patients in this study had died within 30 days of their last 
dose of study drug. Of these patients, 6 died due to disease progression, 1 died due to enlarging 
tumor mass causing tracheal compression, 1 died due to pneumonia, and 2 died due to failure to 
thrive. None of the events were considered related to MLN0128.  
As of the clinical data cutoff date, 55 SAEs had been reported among 29 patients (43%) in this 
study. Overall, 23 patients (49%) reported 1 SAE during the Dose Escalation phase and 6 patients 
(30%) reported 1 SAEs during the Expansion phase.  
The most frequently reported SAEs overall were pneumonia (6 patients), vomiting (2 patients, plus 
hematemesis in 1 patient), small intestinal obstruction (3 patients), and stomatitis, esophageal 
carcinoma, sepsis, and failure to thrive in 2 patients each. SAEs reported in most patients (85%) 
were considered not study drug-related, including all of the fatal events. No SAE event terms were 
reported in >1 patient in the Dose Escalation phase.  
All patients treated in Study INK128-003 reported at least 1 TEAE. Regardless of causality,  
 
events include fatigue, nausea, and diarrhea, which were reported in 67%, 60%, and 52% of 
patients, respectively. 
Regardless of causality, TEAEs reported in 54 patients (81%) overall were assessed as severity 
Grade 3. 
 
hypophosphatemia (15%), diarrhea and hyperglycemia (12% of patients each), and fatigue, 
hypokalemia, and vomiting (10% of patients each).  
All but 1 patient had discontinued from M treatment in Study INK128-003 as of the clinical data 
cutoff. Reasons for discontinuation for the other 66 patients included disease progression (54%), 
patient decision (24%), or 
 TEAE (21%).  


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A total of 21 TEAEs were reported as leading to study discontinuation. Events reported for more 
than 1 patient included fatigue (4 patients) and pneumonia, rash (including erythematous rash), 
failure to thrive, or vomiting (2 patients, each). A majority (52%) of the events were considered 
not related to MLN0128.  
2.4.5 
Study C31001  
Study C31001 is a phase 1b/2 study of the safety and efficacy of MLN0128 in combination with 
exemestane or fulvestrant in women with ER+/HER2  advanced or metastatic breast cancer that 
has progressed on prior treatment with everolimus in combination with exemestane or fulvestrant. 
Patients in this study continue receiving their same prior therapy (either exemestane or fulvestrant) 
at the same dose, in combination with MLN0128. As of the clinical data cutoff date, 16 patients  
 MLN0128 dose along with either exemestane (7 patients) or fulvestrant (9 
patients). A total of 88% of the women treated as of the data cut were white. At baseline, their 
median age was 56.5 years (range 42-74 years). Of the original 16 patients, 12 remained ongoing 
as of data cutoff. 
Deaths 
As of the clinical data cutoff date, no patient had died within 30 days of administration of their last 
dose of study drug.   
Serious Adverse Events 
As of the clinical data cutoff date, 3 treatment-emergent SAEs (ataxia, pneumonitis, and upper 
respiratory tract infection) had been reported in 3 patients (19%). The SAE of ataxia resulted in a 
dose delay, and no action was taken in response to the other events. All 3 events were reported as 
being severity Grade 3 and all had resolved as of the data cut. Only the event of pneumonitis was 
considered related to study drug.   
Treatment-Emergent Adverse Events 
diarrhea or stomatitis, which were reported in 69%, 50%, and 44% of patients, respectively. 
3 were alanine 
aminotransferase increased, diarrhea, fatigue, and nausea, each of which were reported in 2 patients 
Events Leading to Study Discontinuation 
Four patients had discontinued from MLN0128 treatment as of the clinical data cutoff. Reasons 
for discontinuation were disease progression (2 
 TEAEs (1). 
The TEAE leading to discontinuation was Grade 3 nausea in a patient in the MLN0218+fulvestrant 
arm. The event was not considered related to study drug and had resolved as of data cutoff.    
2.4.6 
Study C31002 
Study C31002 is a phase 1 open label, single-arm, multicenter study to evaluate the effect of a 
single dose of 40 mg MLN0128 on the QT/QTc (QT interval corrected for heart rate) in patients 


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with advanced solid tumors. After completing the per-protocol PK/ECG assessments on Cycle 1, 
Day 3, patients may continue to receive MLN0128 if, in the opinion of the investigator, the patient 
is deriving clinical benefit, until they experience disease progression. Patients continuing treatment 
receive MLN0128 30 mg QW in 28-day cycles. As of the clinical data cutoff date, 19 patients had  
 MLN0128 dose in this study and 3 had entered Cycle 2. A total of 53% are women  
and 74% are white. At baseline, their median age was 63.5 years (range, 46-76 years). Of the 
original 19 patients, 16 remained ongoing as of data cutoff. 
Deaths 
As of data cutoff, no reports of events having fatal outcomes had been reported to the clinical 
database as of data cutoff.  
Serious Adverse Events 
Serious adverse event information had not been reported to the clinical database as of the data 
cutoff date. 
Treatment-Emergent Adverse Events 
 
decreased appetite, and vomiting, which were reported in 53%, 42%, 32%, and 21% of patients, 
respectively. Information regarding severity of TEAEs had not been reported to the clinical 
database as of data cutoff. 
Events Leading to Study Discontinuation 
As of data cutoff, 2 
 event was 
pelvic pain. The other event had not been coded as of data cutoff;  Both events were reported as 
being Grade 4 in severity, had not yet resolved as of data cutoff, and were not considered study 
drug-related. 
2.4.7 
Pharmacokinetics 
Overall, pharmacokinetic (PK) data from Studies INK128-001, INK128-002, and INK128-003 
indicate that MLN0128 exhibits fast oral absorption (first time to maximum plasma concentration 
[Tmax], generally between 1-4 hours after dosing); dose-linear PK, with a mean plasma half-life 
(t½) of approximately 8 hours; and that MLN0128 does not accumulate meaningfully in plasma 
when dosed as frequently as once daily and under any of 4 tested dosing regimens. The PK of 
MLN0128 was generally consistent, with no appreciable differences across the 3 clinical studies. 
Neither paclitaxel nor MLN0128 appeared to alter the PK of the other agent when co-administered. 
A capsule containing milled active pharmaceutical ingredient (API) is available for clinical studies 
in 1 mg, 3 mg and 5 mg strengths. The milled API, may result in faster absorption profile with 
possibly higher maximum concentration (Cmax), which could result in a different safety profile 
compared to the previous unmilled API capsules. Therefore, Takeda has ongoing studies with the 
new milled API to determine the recommended phase 2 dose (RP2D) for single agent MLN0128 
and in combination with paclitaxel. 


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2.5 
Rationale  
Recently, a human polyomavirus (MCV) was implicated in the pathogenesis of MCC. MCV is 
constituted by 5,387 base pairs, encoding for the large T (LT) antigen and small T (ST) antigen, 
which act differently and synergistically to promote cell proliferation and transformation [7].  
A key step in cap-dependent translation is the binding of eukaryotic translation initiation factor 4E  
-methylguanosine GTP cap [8]. Ribosome recruitment  
to capped mRNAs is initiated by the assembly of the multi-subunit eIF4F, composed of eIF4E, 
eIF4A, and eIF4G, on the cap. A key regulator of this process is the eukaryotic translation initiation 
factor 4E-binding protein 1 (4E-BP1), which sequesters eIF4E to prevent eIF4F formation on 
capped mRNA [9]. Induction of cap-dependent translation may play a role in tumor cell growth, 
since eIF4E overexpression causes rodent cell transformation [10,11].   
Shuda et al [7] showed that MCV ST antigen reduced turnover of hyperphosphorylated 4E-BP1, 
which in turn increased eIF4E activity. Expression of a constitutively active 4E-BP1 that cannot 
be phosphorylated reversed MCV ST–induced cell transformation, which showed that the 
proliferative effects of MCV ST are caused by targeting downstream components of the AktmTOR 
pathway. These findings indicate that MCV ST targets cap-dependent translation though a 
mechanism that contributes to Merkel cell tumorigenesis. 
Lin et al [8] using tissue microarray and immunohistochemistry, found that mTOR pathway was 
activated as indicated by positive staining of phosphorylation-4E-BP1, phosphorylation-S6K, and 
phosphorylation-mTOR regardless of MCV status. Two primary human MCC cell lines from two 
patients with lymph node metastases were established, demonstrating mTOR pathway 
upregulation and decreased autophagy in both MCC cells. Inhibition of mTOR pathway decreased 
cell proliferation and induced autophagy and cell death in MCC cells. Furthermore, cell death 
induced by mTOR inhibitors was independent of caspase activation and attenuated by an 
autophagy inhibitor, suggesting a rationale for potential new therapeutic targets.  
Finally, Nardi et al [9] retrospectively profiled 60 primary MCC samples using a SNaPshot-based 
tumor genotyping assay to screen for common mutations in 13 cancer genes. Six of 60 were found 
to have PIK3CA gene activating mutations. Sanger sequencing of the primary MCC tumors 
detected one additional PIK3CA mutation (R19K) that had not been previously described in 
cancer. MCV was detected in 38 (66%) MCC cases. With one exception, the presence of MCV 
and activating mutations in PIK3CA appeared mutually exclusive. We observed that signaling 
through the PI3K/pAKT pathway was active in one MCV-positive and in all MCV-negative MCC 
cell lines, as evidenced by AKT phosphorylation.   
MLN0128 is a novel, highly selective, orally bioavailable ATP-competitive inhibitor of the mTOR. 
The mTOR is a kinase that regulates cell growth, translational control, angiogenesis, and cell 
survival. MLN0128 selectively and potently inhibits mTOR kinase, inhibits mTORC1/2 signaling, 
and prevents cellular proliferation. mTORC1 is best known as a key regulator of protein translation 
through phosphorylation of 4EBP1 and ribosomal protein 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 [6].  


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Based on the above data, we propose a run-in phase I prior to the phase II study, to evaluate the 
RP2D; and phase II to determine activity of MLN0128 in patients with metastatic/recurrent MCC. 
PK samples will be obtained on days 8, 15 and 28 in phase I.  
2.6 
Correlative Studies Background 
All patients will have tumor tissue collected (upto 40 unstained slides or one tumor block). A vial 
of EDTA blood will also be obtained. Whole exome sequencing will be performed on tumor and 
normal genomic DNA of all patients. All patients will undergo Oncopanel testing which analyzes 
300 cancer relevant genes. Patients with accessible tumors may undergo sequential biopsies prior 
to, at 4 weeks of therapy and upon progression. Analysis of p4EBP1, pSK6, pCAD, pMTOR and 
MCV LT/ST will be performed retrospectively to correlate with disease response. 
PATIENTS WHO PROGRESS ON THERAPY WILL BE STRONGLY ENCOURAGED TO 
UNDERGO ANOTHER BIOPSY. WHOLE EXOME SEQUENCING WILL BE PERFORMED 
ON THIS SAMPLE TO ELUCIDATE POTENTIAL RESISTANCE MECHANISMS.  
3. UPDATED MANUFACTURING PROCESS 
A new MLN0128 capsule containing milled active pharmaceutical ingredient (API) is available 
for new clinical studies in 1 mg, 3 mg and 5 mg strengths.   
The milled API, may result in faster absorption profile with possibly higher maximum 
concentration (Cmax), which could result in a different safety profile compared to the previous 
unmilled API capsules. Therefore, ongoing studies (C31001, C31002 and , MLN0128-1004 – A 
Phase I, open label study to evaluate the safety, tolerability, and pharmacokinetics of MLN0128 
as a single agent and in combination with paclitaxel in adult patients with advanced non-
hematologuical malignancies-), with the new milled API will determine the recommended phase 
2 dose (RP2D) for single agent MLN0128 (QD and QW) and QD×3days per week in 
combination with paclitaxel, as well as the effect of high-fat meal on the PK of milled API.  
4. CLINICAL SUMMARY OF SAFETY 
4.1 
Special Warnings and Precautions for Use  
4.1.1 
Insulin and Glucose Levels 
Hyperglycemia and hyperinsulinemia are known toxicities associated with inhibition of mTOR 
and related pathways based on nonclinical studies.  
A rise in fasting plasma glucose has been observed as early as 1 to 2 days following oral 
administration of MLN0128. Daily in-home glucose monitoring and early initiation of treatment 
of the hyperglycemia are essential. For subject self-monitoring of blood glucose, a finding of closer 
monitoring of serum glucose and possible intervention. Subjects with Grade 1 hyperglycemia 
(fasting serum glucose [FSG] > the upper limit of the normal range mg/dL) are treated with oral 
hypoglycemic agents (eg, metformin), and subjects with mg/dL) are treated aggressively with oral 


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hypoglycemic agents and/or insulin as clinically indicated. Daily home monitoring and early 
treatment, have resulted in good control of glucose levels for the majority of MLN0128-treated 
subjects who developed hyperglycemia.   
4.1.2 
Cardiac Effects 
Cardiac events (including QT interval corrected for heart rate prolongation and arrhythmias) have 
been infrequently observed in clinical studies of MLN0128. To date, there has been 1 report of 
ventricular fibrillation and cardiac arrest postdose that had a fatal outcome and was assessed as 
related to MLN0128. Routine cardiac monitoring with baseline electrocardiogram (ECG) or 
multigated acquisition (MUGA) scan and on-study ECGs and physical examination constitute the 
core cardiac safety monitoring in all MLN0128 studies.  
For subjects showing any signs of cardiac instability after MLN0128 dosing, additional monitoring 
onsite before clinic discharge should be considered.  
4.1.3 
Renal Function 
Elevations in creatinine (regardless of causality) have been observed in subjects receiving  
MLN0128, all of which have been reversible with drug interruption and/or supportive care with 
IV hydration. Further evaluation of the renal insufficiency with urine electrolytes suggested a 
prerenal etiology with a low fractional excretion of sodium < 1%. However, the adverse event 
cases were confounded by multiple factors such as nausea, vomiting, hyperglycemia, concomitant 
medications with GI side effects such as metformin, and hydronephrosis, any of which may have 
also contributed to dehydration and elevated creatinine. Subjects should be encouraged to drink at 
least 20 ounces of fluids a day, especially on days requiring fasting (per protocol), with 
administration of IV fluids in the clinic as indicated to avoid dehydration.  
Baseline macroscopic urinalysis and routine serum chemistries along with other safety laboratory 
assessments are performed in all MLN0128 studies. Additionally, microscopic urinalysis, a 12 
hour urine collection, spot urine electrolytes, protein and creatinine, and serum chemistry should 
 according to National Cancer 
Institute Common Terminology Criteria for Adverse Events version 4.0, to further evaluate 
possible etiologies for the renal dysfunction.  
4.1.4 
Rash 
Rash observed in clinical studies of MLN0128 tends to be maculopapular and pruritic and has 
ranged from Grade 1 to 3. For the most part, rash and pruritus improve with antihistamines, topical 
steroid creams, and/or dose interruption. Some subjects have required pulse systemic steroids, dose 
reduction, and/or study treatment discontinuation.  
4.1.5 
Pneumonitis  


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Pneumonitis is a known potential risk of mTOR inhibitors. Early recognition, prompt intervention, 
and a conservative risk management approach are recommended due to pneumonitis that has been 
observed with rapalog therapy and with MLN0128 administration. Symptoms of pneumonitis will 
be closely monitored in all MLN0128 study subjects.  
4.2 
Interactions with other medications and other forms of interaction 
Clinical drug-drug interaction studies have not been conducted with MLN0128. At this time, there 
are no known drug interactions. In vitro data, including cytochrome P450 induction/inhibition and 
transporter inhibition studies conducted for MLN0128, suggest a low risk for MLN0128 to 
precipitate a drug-drug interaction. Although potential drug-drug interactions with MLN0128 
cannot be ruled out based on the known metabolism characteristics of MLN0128, the potential risk 
is considered low.  
5. PARTICIPANT SELECTION  
Inclusion Criteria  
Metastatic or recurrent MCC confirmed by histology 
Participants must have measurable disease, defined as at least one lesion that can be 
accurately measured in at least one dimension (longest diameter to be recorded) as > 20 mm 
with conventional techniques or as > 10 mm with spiral CT scan (see section 12 for the 
evaluation of measureable disease). Tumors within a previously irradiated field will be 
designated as “non-target” lesions unless progression is documented                    Age 18 years 
or older  
ECOG performance status 2 (Karnofsky 60%, see Appendix A)  
Participants must have normal organ and marrow function as defined below: 
leukocytes  
3,000/mcL absolute neutrophil count  
1,500/mcL 
 
platelets 
100,000/mcL 
hemoglobin total bilirubin within normal institutional limits AST(SGOT)/ALT(SGPT) 
2.5 × institutional upper limit of normal creatinine within normal institutional limits, OR 
creatinine clearance 60 mL/min/1.73 m2 for participants with creatinine levels above 
institutional normal fasting serum glucose  fasting triglycerides  Female patients who: o Are 
postmenopausal for at least 1 year before the screening visit, OR o Are surgically sterile, OR 
o If they are of childbearing potential, agree to practice 2 effective methods of 
contraception, at the same time, from the time of signing the informed consent  
through 90 days after the last dose of study drug, or agree to completely abstain 
from heterosexual intercourse. Periodic abstinence (calendar, ovulation, 
symptothermal, postovulation methods) and withdrawal are not acceptable methods 
of contraception  
 
 Male patients, even if surgically sterilized (ie, status post-vasectomy), who:  
o Agree to practice effective barrier contraception during the entire study treatment  
period and through 120 days after the last dose of study drug, or  


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o Agree to completely abstain from heterosexual intercourse. Periodic abstinence 
(calendar, ovulation, symptothermal, postovulation methods for the female partner) 
and withdrawal are not acceptable methods of contraception 
o Agree not to donate sperm during the course of this study or 120 days after receiving 
their last dose of study drug.  
 Treatment with strong CYP2C19, CYP3A4, and CYP2C9 inhibitors and/or inducers must be 
discontinued at least 1 week before administration of the first dose of study drug (see 
appendix B)  
 Tissue for correlative studies must be available (paraffinized or frozen), but confirmation at 
screening is not needed. Archival tissue may be used instead of a fresh biopsy at baseline 
if it already exists. 
 Ability to swallow oral medications and maintain an empty stomach state for 2 hours prior to 
the MLN0128 dose and for 1 hour following administration 
 Ability to understand and the willingness to sign a written informed consent document before 
performance of any study related procedure not part of standard medical care 
Exclusion Criteria 
 Participants who have had chemotherapy or radiotherapy within 2 weeks prior to entering the 
study or those who have not recovered from adverse events due to agents administered 
more than 4 weeks earlier  
 The subject has active brain metastases or epidural disease (Note: Subjects with brain 
metastases previously treated with whole brain radiation or radiosurgery or subjects with 
epidural disease previously treated with radiation or surgery who are asymptomatic and do 
not require steroid treatment for at least 2 weeks before starting study treatment are 
eligible).  
Participants who are receiving any other investigational agents within 14 days before the 
first dose of study drug 
Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, 
or psychiatric illness/social situations that would limit compliance with study requirements  
Female patients who are both lactating and breastfeeding or have a positive serum pregnancy 
test during the screening period or a positive urine pregnancy test on Day 1 before first dose 
of study drug   
Manifestations of malabsorption due to prior gastrointestinal (GI) surgery, GI disease, or 
for an unknown reason that may alter the absorption of MLN0128  
Poorly controlled diabetes mellitus defined as HbA1c > 7%; subjects with a history of 
transient glucose intolerance due to corticosteroid administration are allowed in this study if 
all other inclusion/exclusion criteria are met 
 
 History of any of the following within the last 6 months prior to study entry:  
o Ischemic myocardial event, including  angina requiring therapy and artery 
revascularization procedures 
o Ischemic cerebrovascular event, including TIA and artery revascularization 
procedures  


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o Requirement for inotropic support (excluding digoxin) or serious (uncontrolled) 
cardiac arrhythmia (including atrial flutter/fibrillation, ventricular fibrillation or 
ventricular tachycardia)  
o Placement of a pacemaker for control of rhythm 
o New York Heart Association (NYHA) Class III or IV heart failure (See Appendix 
B)    
o Pulmonary embolism  
 
Significant active cardiovascular or pulmonary disease at the time of study entry, including:  
o Uncontrolled high blood pressure (i.e., systolic blood pressure >180 mm Hg, 
diastolic blood pressure > 95 mm Hg)  
o Pulmonary hypertension    
o Uncontrolled asthma or O2 saturation < 90% by ABG (Arterial Blood Gas) analysis 
or pulse oximetry on room air     
o Significant valvular disease; severe regurgitation or stenosis by imaging 
independent of symptom control with medical intervention, or history of valve 
replacement    
o Medically significant (symptomatic) bradycardia     
o History of arrhythmia requiring an implantable cardiac defibrillator   o Baseline 
prolongation of the rate-corrected QT interval (QTc) (e.g., repeated demonstration 
of QTc interval > 480 milliseconds, or history of congenital long QT syndrome, or 
torsades de pointes)   
 
Initiation of treatment with hematopoietic growth factors, transfusions of blood and blood 
products, or systemic corticosteroids (either IV or oral steroids, excluding inhalers) 
within 1 week before administration of the first dose of study drug (patients already  
Diagnosed or treated for another malignancy within 2 years before administration of the 
first dose of study drug, or previously diagnosed with another malignancy and have any 
evidence of residual disease. Patients with nonmelanoma skin cancer or carcinoma in situ 
of any type are not excluded if they have undergone complete resection. 
Inclusion of Women and Minorities 
Both men and women of all races and ethnic groups are eligible for this trial. 
6. 
REGISTRATION PROCEDURES 
6.1 
General Guidelines for DF/HCC and DF/PCC Institutions 
Study team will register eligible participants with the DF/HCC Quality Assurance Office for 
Clinical Trials (QACT) central registration system. Registrations must occur prior to the initiation 
of protocol therapy. Any participant not registered to the protocol before protocol therapy begins 
will be considered ineligible and registration will be denied.  


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An investigator will confirm eligibility criteria and a member of the study team will complete the 
QACT protocol-specific eligibility checklist. 
Following registration, participants may begin protocol therapy. Issues that would cause treatment 
delays should be discussed with the Overall Principal Investigator (PI). If a participant does not 
receive protocol therapy following registration, the participant’s registration on the study must be 
canceled. Notify the QACT Registrar of registration cancellations as soon as possible.   
6.2 
Registration Process for DF/HCC and DF/PCC Institutions 
The QACT registration staff is accessible on Monday through Friday, from 8:00 AM to 5:00 PM 
Eastern Standard Time. In emergency situations when a participant must begin protocol therapy 
during off-hours or holidays, call the QACT registration line at 617-632-3761 and follow the 
instructions for registering participants after hours. 
The registration procedures are as follows: 
 Obtain written informed consent from the participant prior to the performance of any protocol 
specific procedures or assessments.  
 Complete the QACT protocol-specific eligibility checklist using the eligibility assessment 
documented in the participant’s medical record and/or research chart. To be eligible for 
registration to the protocol, the participant must meet all inclusion and exclusion criterion 
as described in the protocol and reflected on the eligibility checklist. 
Reminder: Confirm eligibility for ancillary studies at the same time as eligibility for a 
treatment protocol. Registration to both treatment and ancillary protocols will not be 
completed if eligibility requirements are not met for all studies.  
 Fax the eligibility checklist(s) and all pages of the consent form(s) to the QACT at 617632-
2295. For Phase I protocols, attach participant dose level assignment confirmation from the 
sponsor.  
 The QACT Registrar will (a) review the eligibility checklist, (b) register the participant on 
the protocol, and (c) randomize the participant when applicable. 
 An email confirmation of the registration and/or randomization will be sent to the Overall PI, 
study coordinator(s) from the Lead Site, treating investigator and registering person 
immediately following the registration and/or randomization. 
NOTE: Registration with the QACT can only be conducted during the business hours of 8:00 AM 
and 5:00 PM Eastern Standard Time Monday through Friday. Same day treatment registrations 
will only be accepted with prior notice and discussion with the DF/HCC Lead  
Institution.   


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7. 
TREATMENT PLAN 
7.1 
Treatment Regimen 
MLN0128 milled API will be administered (phase I starting dose, 3mg and phase II starting at 
RP2D), orally, daily at the same time of the day, until disease progression, unacceptable toxicity 
or withdrawal of consent. Dose reduction beyond 2 mg is not allowed. Treatment will be 
administered on an outpatient basis.  Reported adverse events and potential risks are described in 
Section 9.  Appropriate dose modifications are described in Section 8.  No investigational or 
commercial agents or therapies other than those described below may be administered with the 
intent to treat the participant's malignancy. 
The participant will be requested to maintain a medication diary of each dose of medication.  The 
medication diary will be returned to clinic staff at the end of each cycle.  
7.2 
Pre-Treatment Criteria 
As long as the screening lab results meet eligibility criteria, some lab value variance may be 
allowed by Cycle 1 Day 1, as long as toxicity criteria are not met. In the event that the participant’s 
condition is deteriorating, laboratory evaluations should be repeated within 48 hours prior to 
initiation of the next cycle of therapy.  
7.3 
Agent Administration 
All protocol-specific criteria for administration of MLN0128 must be met and documented before 
drug administration. Study drug will be administered only to eligible patients under the supervision 
of the investigator or identified subinvestigator(s).  
MLN0128 capsule will be taken orally, once daily, approximately at the same time each day, on 
an empty stomach. The patients should be instructed to refrain from eating and drinking (except 
for water and any other prescribed medications), for two hours before and one hour after each dose. 
It is recommended that each dose of MLN0128 be given with 8 ounces (240 mL) of water.  
Patients should be instructed to take their study medication at approximately the same time on 
each scheduled dosing day and not to take more than the prescribed dose at any time. Patients 
should swallow the study medication whole and not chew it, open it, or manipulate it in any way 
before swallowing. If a patient does not take their MLN0128 dose within the time frame 
specified (+/- 8h of the QD or QD×3days per week schedule), then the dose should be skipped 
and considered a missed dose. Patients should record any missed doses in their diary  and resume 
drug administration at the next scheduled time with the prescribed dosage. Under no 
circumstance should a patient repeat a dose or double-up doses.  
In the phase I part of this study, the starting dose of 3 mg QD was chosen to account for the 
possibility of increased absorption with MLN0128 capsules based on preliminary MLN0128 
milled API pharmacokinetic data. Each cohort should be evaluated for tolerability after completing 
1 cycle of treatment before proceeding to escalation (4 mg QD or 5 mg QD) or deescalation (2 mg 


Protocol #: Amendment 4 
Version Date: March 18, 2016 
25  
QD). Escalation/de-escalation should not proceed beyond 5 mg QD or below 2 mg QD respectively 
(Table 1). Patients may not re-escalate dose after a dose reduction. 
The phase II part of the study will use the phase II dose or RP2D determined during the phase I 
part of the study 
7.3.1 
Dose Escalation Criteria 
Number of Subjects per Cohort with 
DLT During Treatment Period 
Dose Escalation Decision 
0 out of 3  
Enter 3 subjects at the next dose level. 
1 out of 3 
Enter 3 more subjects at this dose level. 
If no additional DLT, proceed to the next dose 
level.  
If an additional DLT occurs (i.e.  
2 
DLTs/6 subjects), dose escalation is stopped 
and the previous dose level is declared the 
MTD. 
 
The previous dose level is declared MTD. 
There is no advancement to higher dose 
levels. 
7.3.2 
Dose Escalation for Phase I  
Dose level 
MLN0128 Dose 
-1 
2 mg QD 
1 (starting dose) 
3 mg QD 
2 
4 mg QD 
3 
5 mg QD 
If severe emesis or mucositis prevents the patient from taking an MLN0128 dose, that dose will be 
skipped. If emesis occurs after study medication ingestion and whole capsule is visible in the 
vomitus, replacement capsule should be taken; otherwise the dose will not be re-administered, and 
patients should simply adhere to the dosing schedule and resume dosing at the next scheduled time 
with the prescribed dosage. Under no circumstance should a patient repeat a dose or double-up 
doses.  


Protocol #: Amendment 4 
Version Date: March 18, 2016 
26  
7.3.3 
Dose-Limiting Toxicity:  
Toxicity will be assessed using the NCI Common Toxicity Criteria for Adverse Events, version 
4.0 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf 
unless otherwise specified (e.g., hyperglycemia). A dose-limiting toxicity (DLT) is defined as an 
adverse event or abnormal laboratory value assessed as unrelated to disease, disease progression, 
inter-current illness, or concomitant medications, and occurs < 28 days following the last dose of 
MLN0128, and meets any of the criteria listed below.  
Whenever a patient experiences toxicity that fulfills the criteria for a DLT (or a potential DLT), 
treatment with MLN0128 will be interrupted (if not otherwise specified) and the toxicity will be 
followed up as described in section 7.3. 5.  The criteria for dose-limiting toxicities are outlined 
below.  
7.3.4 
Criteria for Defining Dose-Limiting Toxicities 
TOXICITY 
ANY OF THE FOLLOWING CRITERIA 
Hematologic a 
•CTCAE grade 3 neutropenia for > 7 consecutive days 
CTCAE grade 3 thrombocytopenia for > 7 consecutive days 
CTCAE grade 4 thrombocytopenia 
CTCAE grade 3 thrombocytopenia with clinically significant bleeding 
Febrile neutropenia (ANC < 1.0 x 109/L, fever • 38.5°C) 
Renal 
Serum creatinine 2.0 x ULN to ” 3.0 x ULN for > 7 consecutive days 
> CTCAE grade 3 serum creatinine 
Hepatic b 
Total bilirubin 2xULN to ” 3.0 x ULN for > 7 consecutive days 
> CTCAE grade 3 total bilirubin 
CTCAE grade 3 AST or ALT for > 7 consecutive days 
CTCAE grade 4 AST or ALT 
Endocrine 
Grade 2 hyperglycemia (confirmed with a repeat FPG within 24 hours) that 
does not resolve to grade 1 or baseline within 14 consecutive days (after 
initiation of glimepiride, metformin or glibenclamide) 
•Grade 3 hyperglycemia (confirmed with a repeat FPG within 24 hours) 
Metabolic/Labor 
atory 
CTCAE grade 3 asymptomatic amylase and/or lipase, not reversible to 
CTCAE grade 2 for > 7 consecutive days 
CTCAE grade 4 asymptomatic amylase and/or lipase 
Pancreatitis 
•CTCAE grade 2 
Cardiac 
Cardiac toxicityCTCAE grade 3 or cardiac event that is symptomatic or 
requires medical intervention 
Clinical signs of cardiac disease, such as unstable angina or Myocardial 
infarction, or Troponin • CTCAE grade 3 
Neurotoxicity 
•1 CTCAE grade level increase 


Protocol #: Amendment 4 
Version Date: March 18, 2016 
27  
Mood alteration 
CTCAE grade 2 mood alteration that does not resolve to grade 1 within 14 
days despite medical treatment (for Anxiety only, if worsened from 
baseline) CTCAE grade 3 mood alteration 
Dermatologic 
Any phototoxicity CTCAE grade 2, or skin toxicity (rash) resulting in 
interruption of MLN0128 for > 21 consecutive days 
Other adverse 
events 
•CTCAE grade 3 adverse events (excluding CTCAE grade 3 elevations in 
alkaline phosphatase) 
CTCAE grade 4 and 5 toxicities for hematologic and non-hematologic 
toxicities, unless noted for specific exceptions 
a 
• CTCAE grade 3 anemia will not be considered DLT unless judged to be a hemolytic 
process secondary to study drug. • CTCAE grade 3 lymphopenia will not be considered DLT 
unless clinically significant.  
b 
For any grade 3 or 4 hepatic toxicity that does not resolve within 7 days to grade 1 (or 
grade 2 if liver infiltration with tumor present), an abdominal CT scan has to be performed to 
assess if it is related to disease progression.  
A single patient is assumed not to tolerate the dose if he/she experiences at least one DLT. If a 
lower grade AE leads to a dose interruption of more than 7 doses of MLN0128, this AE will be 
considered as DLT.  
If the 2nd occurrence of an initially non-dose limiting toxicity (e.g., grade 3 AST that resolved 
to grade 1 within 7 days at 1st 
occurrence) leads to a dose reduction (Section 8) within 
28 days of the first dose of MLN0128, this will be considered a DLT.  


Protocol #: Original 
Version Date: April 15, 2015 
28 
7.3.5 
Follow up to DLT  
Patients who experience an AE that meets the definition of a DLT during or after completing Cycle 
1 should have their study drug treatment interrupted. If the event resolves to Grade 1 or baseline 
values within 2 weeks of interrupting planned therapy, and in the opinion of the investigator the 
benefits of continuing treatment outweigh the risks posed by the toxicity, patients may continue 
study treatment with MLN0128 at a 20% to 33% dose reduction (ie, dose reduced from 5 mg to 4 
mg [20%];  from 4 mg to 3 mg [25%]; from 3 mg to 2 mg [33%]; or if dose modification is required 
for patients receiving 2 mg QD, then the dosing frequency should be decreased to 5 days per week 
(28% reduction) instead of decreasing the daily dose administered. If study drug dosing is delayed 
for more than 14 consecutive days for MLN0128related toxicity, despite supportive treatment per 
standard clinical practice, the patient should be discontinued from the study treatment and 
complete the follow-up visit within 30 days of the last administration of MLN0128 and continue 
to be followed according to protocol.  
7.4 
General Concomitant Medication and Supportive Care Guidelines 
Because there is a potential for interaction of MLN0128 with other concomitantly administered 
drugs through the cytochrome P450 system, the case report form must capture the concurrent use 
of all other drugs, over-the-counter medications, or alternative therapies.  The Overall PI should 
be alerted if the participant is taking any agent known to affect or with the potential to affect 
selected CYP450 isoenzymes, including CYP2C19, CYP3A4, and CYP2C9. Appendix B presents 
guidelines for identifying medications/substances that could potentially interact with the study 
agent.  
7.5 
Criteria for Taking a Participant Off Protocol Therapy 
Duration of therapy will depend on individual response, evidence of disease progression and 
tolerance. In the absence of treatment delays due to adverse event(s), treatment may continue for 
until one of the following criteria applies:  
Disease progression 
Intercurrent illness that prevents further administration of treatment 
Unacceptable adverse event(s) 
Participant demonstrates an inability or unwillingness to comply with the oral 
medication regimen and/or documentation requirements  
Participant decides to withdraw from the protocol therapy  
General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the judgment of the treating investigator Participants 
will be removed from the protocol therapy when any of these criteria apply.  The reason 


Protocol #: Original 
Version Date: April 15, 2015 
29 
for removal from protocol therapy, and the date the participant was removed, must be 
documented in the case report form (CRF). Alternative care options will be discussed with 
the participant. 
A QACT Treatment Ended/Off Study Form will be filled out when a participant is removed from 
protocol therapy. This form can be found on the QACT website or obtained from the QACT 
registration staff. 
In the event of unusual or life-threatening complications, treating investigators must immediately 
notify the Overall PI, Guilherme Rabinowits, MD at 617-632-3090 or page at 49015. 
7.6 
Duration of Follow Up  
Participants will be followed for two years from study entry or until death, whichever occurs first. 
7.7 
Criteria for Taking a Participant Off Study 
Participants will be removed from study when any of the following criteria apply: Lost 
to follow-up  
Withdrawal of consent for data submission Death 
The reason for taking a participant off study, and the date the participant was removed, must be 
documented in the case report form (CRF).  
A QACT Treatment Ended/Off Study Form will be filled out when a participant comes off study.  
This form can be found on the QACT website or obtained from the QACT registration staff.   
8. 
DOSING DELAYS/DOSE MODIFICATIONS 
Dose delays and modifications will be made as indicated in the following table. The descriptions 
and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 will be utilized for dose delays and dose modifications. A copy of the  
CTCAE version 4.0 can be downloaded from the CTEP website 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
study treatment at a dose reduction. If a dose modification is required for subjects receiving 2 mg, 
then the dosing frequency should be decreased to 5 days per week, instead of decreasing the daily 
dose administered. See table of dose adjustments below according to the schedule applied in this 
protocol. Patients may not re-escalate dose after a dose reduction. Table 1 a: Dose Reductions for 
Phase I 
Dose Level 
Dose 


Protocol #: Original 
Version Date: April 15, 2015 
30 
3 
5 mg  
2 
4 mg  
1 
3 mg 
-1 
2 mg 
-2 
2 mg x 5 days per week  
 
Discontinue 
Level 1 is the starting dose 
 
If patients in the phase I portion of the trial are tolerating their current study drug dose level and 
have completed 1 cycle at this level, intra-patient dose escalation will be allowed to a dose level 
for which there is 4 weeks of safety data demonstrating acceptable tolerability for at least 3 
patients. This evaluation can also be obtained from DFCI protocol 14-223 (PHASE II STUDY OF 
MLN0128 IN THYROID CANCER), which has the same trial design and the same experimental 
agent under investigation, for thyroid cancer patients. Therefore, for example, if there have been 3 
subjects on 4mg in 14-223 without DLTs, subjects on 15-223 are able to be dose escalated from 
3mg to 4mg without waiting for the 4 mg cohort of 15-223 to be completed.  
Patients will be able to enter the next higher dose level if the PI determines that there is a potential 
clinical benefit. This dose escalation will be approved by the PI after discussion with the treating 
oncologist, and then documented in the patient’s visit note. These patients will be closely 
monitored with weekly visits for 4 weeks, with the following procedures performed at each weekly 
visit (+/- 3 days): PE, concurrent medication assessment, vital status, weight, AE assessment, 
performance status, and fasting lab tests which include CBC w/ diff, serum chemistry, phosphorus, 
LDH, PT/INR, PTT, and urinalysis. After completing the 4 week safety monitoring period, these 
patients will then resume the protocol required visit schedule.  
Patients that have been introduced to a dose escalation stay registered in their original cohort, and 
are not part of the new cohort with regards to data collection in the 3+3 study design. Finally 
patients may be dose escalated more than once, as long as they follow the requirements listed 
above.  
Table 1 b: Anticipated MLN0128 Dose Reductions for Phase II 
Dose 
Level 
Dose (X=RP2D) if X is 5 mg Dose (X=RP2D) if X is 4 mg Dose (X=RP2D) if X is 3 mg
1 
X mg 
X mg 
X mg 
-1 
X-1 mg 
X-1 mg 
X-1 mg 
-2 
X-2 mg 
X-2 mg 
X-1 x 5 days per week 
-3 
X-3 mg 
X-2 x 5 days per week 
Discontinue 
-4 
X-3 x 5 days per week 
Discontinue 
 


Protocol #: Original 
Version Date: April 15, 2015 
31 
 
Discontinue 
 
 
Level 1 is the starting dose 
If MLN0128 dosing is delayed for > 28 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.  
See Section 8.1 for management of MLN0128 dosing for specific clinical events. The PI should 
be contacted prior to any dose modification in MLN0128 for any subject in the study. All dose 
reductions will be by one dose level down at a time, unless specified (there is no dose lower than 
2 mg).  
 
8.1 
  Management of Clinical Events  
8.1.1 
 Management of Hyperglycemia  
We will obtain fasting serum glucose (FSG) levels at clinic visits. Guidance for MLN0128 dose 
management in the event of hyperglycemia is provided in the table below.  
Table 2: 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. 
 
Fasting  
blood Initiate oral hypoglycemic 
 
 
sugar 
agent and/or insulin.  
Resume MLN0128 based on  
 
> 250 mg/dL  
timing of recovery:  
 
> 3 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.  
 


Protocol #: Original 
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32 
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. 
150 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. 
a If dose modification is required for subjects receiving 2 mg, then the frequency of dosing should 
be decreased to 5 days/week, rather than decreasing the daily dose administered. In the event that 
any FSG reading performed at the site indicates hyperglycemia (> upper limit of  
 
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 s
 
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.  
8.1.2 
Management of Noninfectious Pneumonitis  
Pneumonitis is a known potential risk of mTOR inhibitors. Early recognition, prompt 
intervention, and a conservative risk management approach are recommended due to 
pneumonitis that has been observed with rapalog therapy and with MLN0128 administration. 
Symptoms of pneumonitis will be closely monitored in all MLN0128 study subjects.  


Protocol #: Original 
Version Date: April 15, 2015 
33 
Guidance for MLN0128 dose management in the event of noninfectious pneumonitis is shown in 
the table below.    
Table 3: Management of Non-infectious Pneumonitis 
Grade 
Description 
Treatment 
MLN0128  
Modification 
Dose  
1 
Asymptomatic: 
Radiographic findings 
only 
Rule out infection and 
closely monitor.  
None. 
2 
Symptomatic: 
Not  
interfering  
ADLs 
with  Rule out infection 
and 
consider 
treatment 
with 
corticosteroids until 
symptoms improve  
Interrupt  
MLN0128 
treatment: 
 
re-initiate 
MLN0128 
treatment at a dose reduction 
 
Grade 1. 
Discontinue  
MLN0128  
treatment  if  
failure  to 
recover within 4 weeks. 
3 
Symptomatic: 
Rule out infection Interrupt MLN0128 treatment  
 
Interfering with ADLs; 
and  
consider  
Requires 
administration 
of O2 
treatment  
with 
corticosteroids until 
symptoms  
improve 
 Grade 1. 
Grade 1. 
Consider  
re-initiating 
MLN0128 treatment at a  
dose reduction   
If toxicity recurs at Grade 3, 
discontinue MLN0128  
 
 
 
treatment. 
 
4 
Life-threatening: 
Ventilatory  support 
indicated 
Rule out infection and 
consider 
treatment  
with 
corticosteroids. 
Discontinue  MLN0128 
treatment. 
 
Abbreviations:  ADL = activities of daily living ; O2 = oxygen gas. 
a If dose modification is required for subjects receiving 2 mg, then the frequency of dosing should 
be decreased to 5 days/week, rather than decreasing the daily dose administered. 
8.1.3 
Management of Hyperlipidemia 
Guidance for MLN0128 dose management in the event of hyperlipidemia is shown in the table 
below.   
Table 4: Management of Hyperlipidemia 
 


Protocol #: Original 
Version Date: April 15, 2015 
34 
Grade 
Description 
Treatment 
MLN0128 Dose Modification 
1 
Cholesterol: 
None. 
None. 
> ULN - 300 mg/dL Triglycerides: 
> 150 - 300 mg/dL 
 
Table 4: Management of Hyperlipidemia 
 
Grade 
Description 
Treatment 
MLN0128 Dose Modification 
2 
Cholesterol: 
Treat hyperlipidemia Maintain dose if tolerable. 
 
> 400 - 500 mg/dL 
Triglycerides: 
> 500 - 1000 mg/dL 
Grade 1, then restart at a dose 
reduction   
4 
Cholesterol: 
> 500 mg/dL 
Triglycerides: 
> 1000 mg/dL 
Same as for Grade 2. 
Same as for Grade 3 
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. 
a If dose modification is required for subjects receiving 2 mg, then the frequency of dosing should 
be decreased to 5 days/week, rather than decreasing the daily dose administered. 
8.1.4 
Management of Oral Mucositis  
Guidance for MLN0128 dose management in the event of oral mucositis is provided in the table 
below.   
Table 5: Management of Oral Mucositis 
 
Grade 
Description 
Treatment 
MLN0128 Dose Modification 
1 
 
Asymptomatic 
or mild 
symptoms 
Non-alcoholic 
mouth 
wash or 0.9% salt water 
rinse; 
Consider  
topical 
corticosteroids at earliest 
signs of mucositis. 
None. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3 
 


Protocol #: Original 
Version Date: April 15, 2015 
35 
 
 
2 
Moderate pain, not 
interfering with oral 
intake  
Topical analgesic mouth 
treatments; 
Topical corticosteroids;  
Maintain dose if tolerable. 
If toxicity becomes intolerable, 
interrupt MLN0128 dosing until  
 
Initiate  
antiviral  
or  
 Grade  
1.   
Modified  diet antifungal  
therapy,  
if Reinitiate at same dose. 
indicated 
indicated. 
 
3 
Severe  
pain, Same as for Grade 2; 
interfering with oral 
intake 
Consider  
intra-
lesional corticosteroids. 
Grade 1, then restart at a dose 
reduction 
4 
Life-threatening 
consequences  
Same as for Grade 2. 
Consider  
intra-
lesional corticosteroids. 
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. 
a If dose modification is required for subjects receiving 2 mg, then the frequency of dosing should 
be decreased to 5 days/week, rather than decreasing the daily dose administered. 
8.1.5 
  Management of Rash  
Guidance for MLN0128 dose adjustment for the event of rash is provided in table below. 
Table 6: Management of Rash  
Grade Description Treatment MLN0128 Dose Modification 2 Macules/papules Consider 
treatment None. 
30% body with topical steroid  
surface area with or 
without symptoms 
cream/ointment 
and/or  oral 
antihistamin
es. 
3 Macules/papules Consider treatment Hold until Grade 2; covering 30% body with 
topical steroid Resume MLN0128 based on  


Protocol #: Original 
Version Date: April 15, 2015 
36 
surface area with or 
without symptoms 
cream/ointment, 
oral antihistamines, 
and/or  pulsed 
steroids.  
timing of recovery:  
 3 weeks: reduce dose ; 
> 3 weeks: stop MLN0128 
and discontinue subject from 
the study. 
 
a If dose modification is required for subjects receiving 2 mg, then the frequency of dosing should 
be decreased to 5 days/week, rather than decreasing the daily dose administered. 
8.1.6 
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 7: Management of Nausea and/or Vomiting 
 
MLN0128  Dose 
Grade
 
Description 
Treatment 
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. 
Inadequate oral intake; within 24 hours  
Maximize 
antiemetic 
therapy; 
Initiate 
tube 
feeding, IVF, or 
TPN. 
Hold until  Grade 1; 
Resume MLN0128 without 
dose modification.  
 
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 
8.1.7 
Management of Cardiac Events 
 
8.1.7.1 
Management of Cardiac Instability 
For subjects showing signs of cardiac instability after MLN0128 dosing, additional monitoring 
onsite before clinic discharge should be considered.  
3 


Protocol #: Original 
Version Date: April 15, 2015 
37 
 
8.1.7.2 
Management of Left Ventricular Dysfunction 
Guidance for MLN0128 dose adjustment for the event of left ventricular dysfunction is provided 
in the table below.  
Table 8: 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 
No change; continue MLN0128 at 
same dose and schedule. 
 
2 
Symptomatic  
cardiac Discontinue treatment. 
dysfunction/congestive heart failure 
Abbreviations:  LLN = lower limit of normal; LVEF = left ventricular ejection fraction. 
 
8.1.7.3 
  Management of QTc Prolongation  
Guidance for MLN0128 dose adjustment for the event of QTc prolongation is provided in the table 
below.  
Table 9: Management of QTc Prolongation 
 
Grade 
Description 
Treatment 
MLN0128 Dose Modification 
2 
480  ms  
 
QTc  
Evaluate for other possible causes 
(eg, electrolyte  
None; continue MLN0128 at the 
same dose and schedule. 
 
 501 ms  
disturbance,  
concomitant  
medication, etc.) 
3 QTc 501 Evaluate for other possible MLN0128 should be ms causes (eg, electrolyte 
interrupted.  
 
disturbance,  
concomitant  
 
medication)a;  
The  
decision  
whether  
to  
Consider a formal consult by a reinitiate MLN0128 treatment 
cardiologist; 
with or without dose reduction Notify the study 
doctor;  
and additional monitoring in Additional  
ECGs  may 
 
be those  
subjects  
who  had  
performed at intervals that the asymptomatic prolonged QTc 
treating  
physician  
deems 501 msec (Grade 3) that has 
clinically  appropriate  
until reverted  to  
an  
acceptable 
repeated QTc measurements interval,  
have  previously fall or 
are below the threshold tolerated MLN0128, and appear interval that 
triggered the repeat to  
have  benefitted  
from measurement.
 
MLN0128 treatment with either disease control or response, will 
be agreed to by the investigator and the study doctor on a caseby-
case basis. 


Protocol #: Original 
Version Date: April 15, 2015 
38 
 
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. 
8.1.8 
Management of Other Nonhematologic Toxicities (including Asthenia, Weakness and 
Fatigue)  
Guidance on dose adjustment for patients with other nonhematologic toxicities is provided below  
Table 10  Management of Other Nonhematologic Toxicities (Including Asthenia, Weakness, and 
Fatigue)  
Grade 
Description 
Treatment 
Dose Modification  
1 
Mild; asymptomatic or Initiate appropriate If tolerable, then no mild 
symptoms; clinical medical therapy and adjustment is required. or diagnostic 
monitor. observations only; intervention not indicated. 
Table 10  Management of Other Nonhematologic Toxicities (Including Asthenia, Weakness, and 
Fatigue)  
Grade 
Description 
Treatment 
Dose Modification 
2 
Moderate; minimal,  
Initiate appropriate  
If tolerable, no local or 
noninvasive  
medical therapy and  adjustment required.  
 
intervention indicated.  
monitor.  
If toxicity becomes  
intolerable, hold  
MLN0128 until recovery  
 
reinitiate at same dose.  
 
Severe or medically 
significant but not 
immediately 
lifethreatening; 
hospitalization or 
prolongation of 
hospitalization indicated 
Hold 
 
MLN0128 
until 
 Grade 
1. 
Reinitiate MLN0128 at dose 
reduced by 1 level  
 
8.1.9 
Management of Aspartate Aminotransferase/Alanine Aminotransferase Elevations  


Protocol #: Original 
Version Date: April 15, 2015 
39 
Guidance on dose adjustment for patients with AST/ALT elevations is provided below  
Table 11         Management of Aspartate Aminotransferase/Alanine  
Aminotransferase Elevations  
Grade 
Description 
Treatment 
Dose Modification 
1 
>ULN to 3 ULN 
None 
None 
2 
Asymptomatic with levels  
 
Closely monitor LFTs at  None 
3 
to 5 ULN; >3 ULN with  least weekly or more the appearance of worsening  
frequently as 
indicated. fatigue, nausea, vomiting,  
 
Assess patient for other right upper quadrant pain 
or  
causes of transaminitis (eg, tenderness, fever, rash, or  
past medical history, 
eosinophilia.  
concomitant medications).  
3 
>5 to 20 ULN; >5 ULN  
Same as for Grade 2.  
Hold MLN0128 
 1; for >2 
weeks Restart MLN0128 at the same  
dose; 
4 
>20 ULN 
Same as for Grade 2.  
Stop MLN0128 and discontinue  
patient from the study.  
Prevention/Prophylaxis: 
Ensure proper screening of patients for study participation. 
 
LFTs=liver function tests, ULN=upper limit of normal. 
Table 11         Management of Aspartate Aminotransferase/Alanine Aminotransferase 
Elevations  
 
 
8.2 
Excluded Concomitant Medications and Procedures 
The following medications and procedures are prohibited during the study:  
Other investigational agents or mTOR inhibitors 
Other anticancer therapies including chemotherapy, immunotherapy, radioimmunotherapy, 
targeted agents, radiation or surgery (subjects can have palliative radiation or surgery in the 
study for pre-existing lesions) 
Systemic corticosteroids (either IV or oral steroids, excluding inhalers), unless necessary 
for treatment of MLN0128 related AE, ie, rash  
Anti-epileptic drugs for subjects with treated brain metastasis 
Anti-emetic drugs that are associated with a risk for QT prolongation, including 
ondansetron  
Concomitant administration of any PPI is not permitted during the study. Patients 
receiving PPI therapy before enrollment must stop using the PPI for 7 days before their first 
dose of study drugs. Examples of PPIs include omeprazole, esomeprazole, pantoprazole, 
lansoprazole, and rabeprazole.  
 
 
 
 


Protocol #: Original 
Version Date: April 15, 2015 
40 
 Strong CYP3A4 and CYP2C19 inducers and/or inhibitors and moderate inhibitors of 
CYP2C9. Consumption of grapefruit or grapefruit juice is not permitted during the study. 
Patients should not consume food or beverages containing the fruit or juice of grapefruits 
or Seville oranges within 7 days before the first dose of study drug and throughout the 
study (see appendix C).   
If a subject requires treatment with 1 or more of the strong CYP3A4 and CYP2C19 inhibitors 
and/or inducers, the study doctor should be consulted.   
 
8.3 
Permitted Concomitant Medications and Procedures  
Prophylactic use of anti-emetic, antinausea, and antidiarrheal medications is encouraged and may 
be used prior to first dose of MLN0128, and as needed throughout the study prior to each dosing 
and as clinically indicated per standard practice. When selecting an anti-emetic agent, drugs that 
do not have an effect on the QT interval, such as palonosetron, are preferred.  
Prophylactic use of anti-emetic, antinausea, and antidiarrheal medications is encouraged, and 
these may be administered before the first dose and subsequent doses of study drug, as needed 
throughout the study, and as clinically indicated per standard practice. When selecting an 
antiemetic agent, drugs that do not have an effect on the QT interval, such as palonosetron, are 
preferred. 
Histamine H2 receptor antagonists may be allowed, if needed provided that the histamine H2 
receptor antagonist is not taken within 12 hours before and within 6 hours after study drug 
administration. Patients receiving histamine H2 receptor antagonists before enrollment must stop 
using these medications for at least 24 hours before their first dose of study drug. Examples of 
histamine H2 receptor antagonists include ranitidine, famotidine, nizatidine, and cimetidine. 
Neutralizing antacid preparations (acid neutralizers) and calcium supplements are not permitted 
during Cycle 1 on study drug administration days in the phase 1/1b portion of the study, but may 
be taken as needed on non-MLN0128 administration days. However, for all other cycles in the 
phase 1b portion of the study and throughout the phase 2 portion of the study, administration of 
neutralizing antacids and calcium preparations is permitted except from 2 hours before until 2 
hours after MLN0128 administration. Some anti-gas preparations may also have antacid 
properties, and should also not be permitted from 2 hours before until 2 hours after study drug 
administration. 
Strong CYP3A4 and CYP2C19 inducers and/or inhibitors and moderate inhibitors of CYP2C9 
should only be administered with caution, at the discretion of the investigator (see Appendix X).  
 
8.4 
Precautions and Restrictions  
No dietary restrictions will be imposed on study patients other than avoiding the fruit or juice from 
grapefruit and Seville oranges within 1 week before first dose of study drug and throughout the 
study and daily fasting for glucose monitoring.  


Protocol #: Original 
Version Date: April 15, 2015 
41 
Patients who show evidence of hyperglycemia during the study should be encouraged to follow a 
low carbohydrate diet. 
Pregnancy 
It is not known what effects MLN0128 has on human pregnancy or development of the embryo or 
fetus.  Therefore, female patients participating in this study should avoid becoming pregnant, and 
male patients should avoid impregnating a female partner.  Nonsterilized female patients of 
reproductive age group and male patients should use effective methods of contraception through 
defined periods during and after study treatment as specified below.  
Female patients must meet 1 of the following:  
Postmenopausal for at least 1 year before the screening visit, or 
Surgically sterile, or 
If they are of childbearing potential, agree to practice 2 effective methods of 
contraception from the time of signing of the informed consent form through 90 days (3 months) 
after the last dose of study drug, or agree to completely abstain from heterosexual intercourse. 
Male patients, even if surgically sterilized (ie, status post-vasectomy) must agree to 1 of the 
following:  
 Practice effective barrier contraception during the entire study treatment period and through 
90 days (3 months) after the last dose of study drug, or completely abstain from 
heterosexual intercourse. 
 b-HGG testing for women of childbearing potential should be done prior to the initiation of 
each cycle. 
9. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The following 
list of reported and/or potential AEs (Section 9.1) and the characteristics of an observed AE 
(Section 9.2) will determine whether the event requires expedited reporting in addition to routine 
reporting. 
9.1 
Expected Toxicities 
All the events included in this section are considered expected for the purpose of regulatory 
reporting and must remain unchanged. Adverse drug reactions that have a reasonably causal 
relationship to treatment with MLN0128 are presented in table below, listed according to Medical 
Dictionary for Regulatory Activities (MedDRA) System Organ Class and Preferred Term. 


Protocol #: Original 
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42 
Gastrointestinal Disorders 
Diarrhea 
Nausea 
Stomatitis 
Vomiting 
General Disorders and Administration Site Conditions 
Asthenia  
Fatigue 
Mucosal inflammation 
Metabolism and Nutrition Disorders 
Anorexia  
Decreased appetite 
Hyperglycemia 
Skin and Subcutaneous Tissue Disorders 
Pruritus 
Rash 
9.2 
Adverse Event Characteristics 
 
CTCAE term (AE description) and grade:  The descriptions and grading scales found in 
the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 
will be utilized for AE reporting.  All appropriate treatment areas should have access to a 
copy of the CTCAE version 4.0.  A copy of the CTCAE version 4.0 can be downloaded 
from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
 
For expedited reporting purposes only:   
- 
AEs for the agent that is listed above should be reported only if the adverse 
event varies in nature, intensity or frequency from the expected toxicity 
information which is provided.  
- 
Other AEs for the protocol that do not require expedited reporting are outlined 
in the next section (Expedited Adverse Event Reporting) under the sub-heading 
of ProtocolSpecific Expedited Adverse Event Reporting Exclusions.  
 
 
Attribution of the AE:  
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 


Protocol #: Original 
Version Date: April 15, 2015 
43 
9.3 
Routine Adverse Event Reporting 
All Adverse Events must be reported in routine study data submissions to the Overall PI on the 
toxicity case report forms. AEs reported through expedited processes (e.g., reported to the IRB, 
FDA, etc.) must also be reported in routine study data submissions. 
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 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 time of consent up to and 
including 30 days after administration of the last dost 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 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 sponsor-investigator Guilherme Rabinowits, MD, 
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 IRB. Regardless of 
expectedness or causality, all SAEs must also be reported to Millennium Pharmacovigilance or 
designee: 
Fatal and Life Threatening SAEs: within 24 hours but no later than 4 calendar days of the sponsor-
investigator’s observation or awareness of the event.  
All other serious (non-fatal/non life threatening) events: within 4 calendar days of the 
sponsorinvestigator’s observation or awareness of the event. See below for contact information 
for the reporting of SAEs to Millennium Pharmacovigilance. 
The SAE report must include at minimum: 
Event term(s) Serious criteria; Intensity of the event(s): Sponsor-investigator’s or 
subinvestigator’s determination. Intensity for each SAE, including any lab abnormalities, will be 
determined by using the NCI CTCAE version specified in the protocol, as a guideline, whenever 
possible. The criteria are available online at http://ctep.cancer.gov/reporting/ctc.html.Causality of 
the event(s): Sponsor-investigator’s or sub-investigator’s determination of the relationship of the 
event(s) to study drug administration. 
Follow-up information on the SAE may be requested by Millennium.  


Protocol #: Original 
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44 
Sub-investigators must report all SAEs to the sponsor-investigator so that the sponsorinvestigator 
can meet his/her foregoing reporting obligations to the required regulatory agencies and to 
Millennium Pharmacovigilance, unless otherwise agreed between the sponsor-investigator and 
sub-investigator(s).  
Relationship to study drug for each SAE will be determined by the investigator or 
subinvestigator 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 drug product as soon 
as possible but no later than 4 calendar days of such communication.  
SAE and Pregnancy Reporting Contact Information: 
Cognizant  
Fax Number: 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  
9.3.1 
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events: 
If a woman becomes pregnant or suspects that she is pregnant while participating in this study, 
she must inform the investigator immediately and permanently discontinue study drug. The 
sponsor-investigator must fax a completed Pregnancy Form to the Millennium Department of 
Pharmacovigilance or designee. The pregnancy must be followed for the final pregnancy 
outcome.  
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 Report 
Form to the Millennium Department of Pharmacovigilance or designee. Every effort should be 
made to follow the pregnancy for the final pregnancy outcome.  
10. 
PHARMACEUTICAL INFORMATION 
A list of the adverse events and potential risks associated with the investigational agent 
administered in this study can be found in Section 9.1. The DFCI INV 100 policy will be followed 
in handling the IP and the destruction of patient returns.  
 
10.1 
MLN0128  


Protocol #: Original 
Version Date: April 15, 2015 
45 
10.1.1 Description 
A new MLN0128 capsule is available in 3 dose strengths, 1 mg, 3 mg, and 5 mg, each containing 
1 mg, 3 mg, and 5 mg of MLN0128, respectively, in addition to the milled active pharmaceutical 
ingredient (API), the following inactive ingredients: microcrystalline cellulose (solid 
filler/diluents), magnesium stearate (lubricant) are found in the, and hard gelatin capsule. All 3 
dose strengths are formulated into size 2 capsules, and each dose strength is differentiated by color, 
as listed below: 
MLN0128 capsules, 1 mg - white opaque color  
MLN0128 capsules, 3 mg – orange opaque color; and/or 
MLN0128 capsules, 5 mg – grey opaque color   
The milled API, may result in faster absorption profile with possibly higher maximum 
concentration (Cmax), which could result in a different safety profile compared to the previous 
unmilled API capsules. Therefore, ongoing studies (C31001, C31002 and , MLN0128-1004 – 
A Phase I, open label study to evaluate the safety, tolerability, and pharmacokinetics of 
MLN0128 as a single agent and in combination with paclitaxel in adult patients with advanced 
non-hematologuical malignancies-), with the new milled API will determine the recommended 
phase 2 dose (RP2D) for single agent MLN0128 (QD and QW) and QD×3days per week in 
combination with paclitaxel, as well as the effect of high-fat meal on the PK of milled API.  
10.1.2 Form 
MLN0128 capsules are packaged in 60-cc HDPE bottles with polypropylene, child-resistant caps 
and induction seal. For all 3 dose strengths, each bottle contains 30 capsules. 
10.1.3 Storage and Stability  
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. 
MLN0128 will be packaged and labeled according to all regulations. Sites must store according to 
the labeled conditions.   
10.1.4 Handling 
Because MLN0128 is an investigational agent, it should be handled with due care. In case of 
contact with broken capsules, raising dust should be avoided during the clean-up operation. The 
product may be harmful if inhaled, ingested, or absorbed through the skin.  
Gloves and protective clothing should be worn during the clean-up operation. The area should be 
ventilated and the spill site washed after material pick-up is complete. The spilled material should 
be disposed of as hazardous medical waste in compliance with federal, state, and local regulations. 
In case of contact with the powder (eg, from a broken capsule), skin should be washed immediately 
with soap and copious amounts of water for at least 15 minutes. In case of contact with the eyes, 


Protocol #: Original 
Version Date: April 15, 2015 
46 
copious amounts of water should be used to flush the eyes for at least 15 minutes. Medical 
personnel should be notified.  
10.1.5 Availability 
MLN0128 will be supplied free-of-charge, by Millennium Pharmaceuticals. 
10.1.6 Preparation  
MLN0128 study drug will be provided in 60 cc high-density polypropylene (HDPE) bottles with 
polypropylene, child-resistant caps and induction seal. Study drug will be dispensed with dosing 
instructions for home use, including the requirement that capsules are stored in their original 
containers and that capsules be swallowed whole and not opened, chewed, or manipulated in any 
way. Materials provided by the sponsor should be dispensed to patients with clear administration 
instructions from the investigator. 
MLN0128 is an anticancer drug and, as with other potentially toxic compounds, caution should be 
exercised when handling MLN0128 capsules.  
10.1.7 Administration 
MLN0128 will be administered once daily, approximately at the same time each day, on an empty 
stomach. The patients should be instructed to refrain from eating and drinking (except for water 
and any other prescribed medications), for two hours before and one hour after each dose. It is 
recommended that each dose of MLN0128 be given orally with 8 ounces (240 mL) of water. 
Missed or vomited dose should not be made up. If patient forgets MLN0128 dose until after 6:00 
pm, he/she should wait until the next day. If the patient vomits MLNM0128 after taking and whole 
capsule is visible in the vomitus, replacement capsule should be taken, otherwise the dose should 
not be re-administered, and patient should simply adhere to the dosing schedule and resume dosing 
at the next scheduled time with the prescribed dosage. Under no circumstance should a patient 
repeat a dose or double-up doses.   
10.1.8 Ordering 
Dana-Farber Research Pharmacy will request supply of MLN0128 capsules form Millennium 
Pharmaceuticals, by submitting the order form. 
10.1.9 Accountability 
Accountability for MLN0128 at the study site is the responsibility of the sponsor-investigator.  
Study drug will be dispensed only to eligible patients by Dana-Farber Research Pharmacy.  The 
appropriate study personnel will maintain records of study drug receipt and dispensing at 
DanaFarber Research Pharmacy. A careful record of the inventory and disposition of the agent 
will be maintained, using the NCI Drug Accountability Record Form (DARF).  


Protocol #: Original 
Version Date: April 15, 2015 
47 
10.1.10 Destruction and Return 
Unused supplies and any expired supplies of the agent will be destroyed on site, by the DanaFarber 
Research Pharmacy.  
11. 
BIOMARKER STUDIES 
We plan to analyze the p4EBP1, PSK6, pCAD and Merkel cell polyomavirus (MCV) Large T 
antigen (LT) and small T antigen (ST) of patients’ biopsy-tumors pre-treatment and correlate with 
treatment benefit. Original archival biopsy can be used instead of the fresh biopsy at baseline, if 
enough tissue is available, otherwise those with easily accessible tumor tissue from minimally 
invasive biopsy sites (e.g. superficial nodes, cutaneous lesions, bone biopsies, superficial soft 
tissue, abdominal ascites and pleural effusions) will be eligible for these biopsies. Formalin fixed 
paraffin embedded (FFPE) samples will be scored for p4EBP1, PSK6, pCAD and MCV LT and 
ST. Clinical efficacy of MLN0128 treatment will then be correlated to high and low expressing 
levels pre-treatment. Upon progression of disease, patients will be asked to provide another biopsy 
(if easily accessible, through minimally invasive procedure) to repeat the above correlative studies. 
This biopsy will be optional and not a requirement to participate on this study.  
MCC sample processing 
All MCC tumor specimens have been handled by our clinical research coordinator, in 
Dermatology.  A protocol is already in place to request tumor blocks and whole blood for research 
purposes. This might be the best way to coordinate this study with earlier MCC studies. MCC 
specimens will have reviewed by BWH Dermatopathology for confirmation of MCC diagnosis 
including review or performance of specialized Immunohistochemistry (IHC) stains for CK20.  
FFPE blocks of MCC tumor specimens will be requested and delivered to the DF/HCC Specialized 
Histopathology Services Core facility at Brigham and Women’s Hospital. The BWH core or 
another laboratory will perform IHC from MCC specimens and will prepare sections or cores to 
extract DNA. 
IHC 
Staining will be performed in non-CLIA format by BWH core. Five unstained 4-micron sections 
will be obtained. Slides will be stained with antibodies for the above targets. 
Whole exome sequencing  
To better understand the biology of the disease, we plan to perform whole exome sequencing of 
available tumor tissue. Whole-exome sequencing is a diagnostic test for patients with nonspecific 
or unusual disease presentations of possible genetic cause and for patients with clinical diagnoses 
of different and unrelated genetic conditions. The purpose is also to study how DNA, genes, 
proteins, and other molecules in the tumor may affect response to treatment. In case archival biopsy 
sample is not available, patients would be asked for an optional fresh tumor biopsy sample during 
screening and at progression. Whole exome sequencing will be performed/coordinated at Broad 
Institute. The goal is to obtain 100-500ng of genomic DNA from FFPE blocks. To obtain sufficient 
amount of DNA, we need one of the following:  


Protocol #: Original 
Version Date: April 15, 2015 
48 
a) 5-10 unstained 10 micron FFPE slides (10 ideal)  
b) 2-3 30 micron scrolls (3 ideal)  
c) 2 x 1mm cores or equivalent (3 x 0.6mm cores, 1 x 2mm core, etc)  
In addition, one tube of whole blood (frozen at – 80°C or fresh) needed for isolation of normal 
blood.  
12. 
STUDY CALENDAR 
Screening evaluations are to be conducted within 4 weeks prior to start of protocol therapy.  Scans 
and x-rays must be done <4 weeks prior to the start of therapy.  In the event that the participant’s 
condition is deteriorating, laboratory evaluations should be repeated within 48 hours prior to 
initiation of the next cycle of therapy. 
With the exception of EKGs, assessments may be done within 24-48 hours of dosing with 
MLN0128 administration. Cycle 1, Day 1 labs do not need to re-meet eligibility criteria for the 
trial. 
Each treatment cycle is 28 days long. Patients will visit the clinic on Days 1, 8, 15 and 22 in cycle 
1 and 2, on Days 1 and 15 in cycle 3 and 4 and on Day 1 in all subsequent cycles. 
Assessments must be performed prior to administration of study agent. Study assessments and 
agent should be administered within + 3 days of the protocol-specified date, unless otherwise 
noted.  
If patients in the phase I portion of the trial are tolerating their current study drug dose level and 
have completed 1 cycle at this level, intra-patient dose escalation will be allowed to a dose level 
for which there is 4 weeks of safety data demonstrating acceptable tolerability for at least 3 
patients. This evaluation can also be obtained from DFCI protocol 14-223 (PHASE II STUDY OF 
MLN0128 IN THYROID CANCER), which has the same trial design and the same experimental 
agent under investigation, for thyroid cancer patients. Therefore, for example, if there have been 3 
subjects on 4mg in 14-223 without DLTs, subjects on 15-223 are able to be dose escalated from 
3mg to 4mg without waiting for the 4 mg cohort of 15-223 to be completed.  
Patients will be able to enter the next higher dose level if the PI determines that there is a potential 
clinical benefit. This dose escalation will be approved by the PI after discussion with the treating 
oncologist, and then documented in the patient’s visit note. These patients will be closely 
monitored with weekly visits for 4 weeks, with the following procedures performed at each weekly 
visit (+/- 3 days): PE, concurrent medication assessment, vital status, weight, AE assessment, 
performance status, and fasting lab tests which include CBC w/ diff, serum chemistry, phosphorus, 
LDH, PT/INR, PTT, and urinalysis. After completing the 4 week safety monitoring period, these 
patients will then resume the protocol required visit schedule.  


Protocol #: Original 
Version Date: April 15, 2015 
49 
Patients that have been introduced to a dose escalation stay registered in their original cohort, and 
are not part of the new cohort with regards to data collection in the 3+3 study design. Finally 
patients may be dose escalated more than once, as long as they follow the requirements listed 
above.  
 
Screening 
 
Cycle 1 & 2 
Cycle 3-4  Cycle 
5+  
EOT 
FU until 
first  
progressioni  
 
 weeks 
of  
treatment 
D1 D8 D15 D22 D1 D15 
D1 
 
 
Informed 
Consent 
X  
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
Concurrent  
Meds 
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
Physical Exama 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Performance 
Status 
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
CBC w/ diff, 
plts 
X  
X  
X  
X   
X   
X  
X  
 
Phosphorus 
X 
X 
X 
X 
 
X  
X 
X 
 
LDH 
X 
X 
X 
X 
 
X  
X 
X 
 
HbA1cb 
X 
X  
 
 
X  
X 
 
 
Serum  
Chemistry 
X  
X  
X  
X   
X   
X  
X  
 
PT/INR, PTT 
X 
X  
X 
 
X  
X 
X 
 
O2 Saturation 
X 
 
 
 
 
 
 
 
 
 


Protocol #: Original 
Version Date: April 15, 2015 
50 
B-HCG 
X 
X  
 
 
X  
X 
X 
 
EKGf 
X 
 
 
 
 
 
 
 
X 
 
PET/CTc; CTc; 
X 
 
X 
X 
X 
X 
X 
MRIc 
 
 
 
 
 
 
Tumor  
Measurementsd  
X  
X  
X  
X  
X  
MLN0128 
 
X 
 
 
Adverse Eventse  
X 
X 
X 
X 
X 
X 
X 
X 
 
Fasting serum 
glucoseg  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
In-home daily 
fasting glucose 
monitoringh  
 
X  
X  
X  
X  
X  
X  
X  
X  
 
Fasting lipid 
profile 
X  
X   
 
 
X   
X  
X  
 
Urinalysis 
X 
X 
 
X 
 
X 
X 
X 
X 
 


Protocol #: Original 
Version Date: April 15, 2015 
51 
a) Physical exam is symptom directed 
b) HbA1c is done every 3 months until first progression, death, or 24 months from study 
entry, whichever occurs first (Screening, C1D1, C3D1, C6D1, C9D1...etc.)  
c) The same imaging modality should be used throughout the study. Scans are done every 2 
cycles until first progression, death, or 24 months from study entry whichever occurs first. 
d) Tumor measurements should be done after each scan  
e) Patients will be assessed on every cycle for adverse events until first progression, death, or 
24 months from study entry, whichever occurs first  
f) EKGs are done only at screening and EOT. 
g) Fasting serum glucose will be measured at each clinic visit. Patients are required to fast 
overnight (nothing except water and/or medications after midnight or for a minimum of 8 
hours before the assessment) for each of these measurements. 
h) In-home glucose monitoring is not required on days when fasting glucose is measured in 
the clinic. Patients are required to fast overnight (nothing except water and/or medications 
after midnight or for a minimum of 8 hours before the assessment) for each of these 
measurements. If glucose levels stay low (<150) for 2 consecutive months, glucose 
monitoring can be changed to once a week. 
i) After EOT, tumor assessments/scans are to continue every 2 months until first 
progression, death, or 24 months from study entry, whichever happens first.  
AFTER FIRST PROGRESSION, PARTICIPANTS WILL BE FOLLOWED BY PHONE ONLY, 
EVERY 3 MONTHS (+/- 2 WEEKS) FOR 24 MONTHS FROM STUDY ENTRY OR UNTIL 
DEATH, WHICHEVER OCCURS FIRST. 
13. 
MEASUREMENT OF EFFECT  
13.1 
Antitumor Effect – Solid Tumors 
For the purposes of this study, participants should be re-evaluated for response every 8 weeks.  In 
addition to a baseline scan, confirmatory scans should also be obtained 8 weeks following initial 
documentation of objective response.  
Response and progression will be evaluated in this study using the new international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) 
[Eur J Ca 45:228-247, 2009].  Changes in the largest diameter (unidimensional measurement) of 
the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in the 
RECIST criteria. 
13.1.1 Definitions 
Evaluable for Target Disease response. Only those participants who have measurable 
disease present at baseline, have received at least one cycle of therapy, and have had their 
disease re-evaluated will be considered evaluable for target disease response.  These 
participants will have their response classified according to the definitions stated below.  


Protocol #: Original 
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52 
(Note:  Participants who exhibit objective disease progression prior to the end of cycle 1 
will also be considered evaluable.)  
Evaluable Non-Target Disease Response.  Participants who have lesions present at baseline 
that are evaluable but do not meet the definitions of measurable disease, have received at 
least one cycle of therapy, and have had their disease re-evaluated will be considered 
evaluable for non-target disease.  The response assessment is based on the presence, 
absence, or unequivocal progression of the lesions.   
13.1.2 Disease Parameters 
Measurable disease.  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as  20 mm by chest 
x-ray or 
10 mm with CT scan, MRI, or calipers by clinical exam.  All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters). 
Note: Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable.  
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a 
lymph node must be 15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm).  At baseline and in follow-up, only 
the short axis will be measured and followed.  
Non-measurable disease.  All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with 10 to <15 mm short axis), 
are considered non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
abdominal masses (not followed by CT or MRI), and cystic lesions are all considered 
nonmeasurable. 
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts should 
not be considered as malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts. 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if noncystic 
lesions are present in the same participant, these are preferred for selection as target lesions.  
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target lesions 
and recorded and measured at baseline.  Target lesions should be selected on the basis of 
their size (lesions with the longest diameter), be representative of all involved organs, but 
in addition should be those that lend themselves to reproducible repeated measurements. It 
may be the case that, on occasion, the largest lesion does not lend itself to reproducible 


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53 
measurement in which circumstance the next largest lesion which can be measured 
reproducibly should be selected. A sum of the diameters (longest for non-nodal lesions, 
short axis for nodal lesions) for all target lesions will be calculated and reported as the 
baseline sum diameters. If lymph nodes are to be included in the sum, then only the short 
axis is added into the sum. The baseline sum diameters will be used as reference to further 
characterize any objective tumor regression in the measurable dimension of the disease.   
Non-target lesions.  All other lesions (or sites of disease) including any measurable lesions 
over and above the 5 target lesions should be identified as non-target lesions and should 
also be recorded at baseline. Measurements of these lesions are not required, but the 
presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow up.   
13.1.3 Methods for Evaluation of Disease 
All measurements should be taken and recorded in metric notation using a ruler, calipers, 
or a digital measurement tool.  All baseline evaluations should be performed as closely as 
possible to the beginning of treatment and never more than 4 weeks before the beginning 
of the treatment. 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam.  
Clinical lesions. Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and 10 mm in diameter as 
assessed using calipers (e.g., skin nodules).  In the case of skin lesions, documentation by 
color photography, including a ruler to estimate the size of the lesion, is recommended.   
Chest x-ray. Lesions on chest x-ray are acceptable as measurable lesions when they are  
clearly defined and surrounded by aerated lung; however, CT is preferable.  
Conventional CT and MRI. This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT thickness is 5mm or less. If CT scans have slice thickness 
greater than 5 mm, the minimum size of a measurable lesion should be twice the slice 
thickness. MRI is also acceptable in certain situations (e.g. for body scans).    
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement.  Furthermore, the 
availability of MRI is variable globally.  As with CT, if an MRI is performed, the technical 
specifications of the scanning sequences used should be optimized for the evaluation of the 
type and site of disease.  Furthermore, as with CT, the modality used at follow-up should 


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54 
be the same as was used at baseline and the lesions should be measured/assessed on the 
same pulse sequence.  It is beyond the scope of the RECIST guidelines to prescribe specific 
MRI pulse sequence parameters for all scanners, body parts, and diseases.  Ideally, the 
same type of scanner should be used and the image acquisition protocol should be followed 
as closely as possible to prior scans.  Body scans should be performed with breath-hold 
scanning techniques, if possible.  
FDG-PET/CT Imaging.   
Patient Preparation 
Patients should avoid any strenuous exercise for 24 hours prior to the PET scan and fast 
for no less than 4 hours prior to the injection of FDG. Patients must have a fasting blood  
 200 mg/dL prior to FDG injection. An attempt should be initially made to  
control the blood glucose level, which will require the rescheduling of the injection. If the 
glucose level cannot be controlled (i.e. > 200 mg/dL), the patient will not be included in 
the FDG-PET/CT imaging. Patients should be adequately hydrated with plain water. 
Weight (kg), height (cm), and blood glucose (mg/dL) will be measured and recorded prior 
to the injection of FDG. Sedation (alprazolam, 0.5-1 mg, po, 30 minutes pre-FDG 
injection) is allowed, but not mandatory and should be used consistently by the patient for 
all scans. Filgrastim, pegfilgrastim, and epoetin are known to affect FDG uptake, and their 
use by the patient should be recorded. Patients should wait in a warm room to avoid false 
positive brown fat FDG uptake. Patients will lie supine in a quiet room during the FDG 
uptake period. FDG will be synthesized and prepared in accordance with the institution’s 
standard procedures or obtained from a commercial supplier.  
FDG Dosing and Administration 
The administered activity of FDG should be based on the PET/CT system manufacturer’s 
recommendation. The recommended FDG dose is 0.14-0.21 mCi/kg. The actual FDG dose 
should be a bolus of 8-20 mCi, followed by a saline flush (per institutional procedure). 
Preinjection FDG Syringe dose, FDG dose injected and Post-injection FDG dose residual 
and corresponding time should be documented.  
FDG-PET/CT Imaging Acquisition   
Whole body PET/CT acquisition at both pre-therapy (baseline) and on follow ups MUST 
start 70 (± 10) minutes after FDG injection. The timing should stay the same for followup 
PET/CT scans from the baseline (no more than a ± 10 minute difference). It is critical that 
follow-up PET/CT scans will be performed in an identical way to the baseline scan, with 
the same scanner, same scan direction (skull to thighs or thighs to skull), and consistent 
arm positioning (arms up or arms down). Preferably, schedule the patient for both baseline 
and follow-up scans at the same time of day (AM or PM) to improve reproducibility. The 
field of view is to encompass the region between the scalp and toes. Patient will be scanned 
supine with arms positioned comfortably above the head, if possible. Oral and/or IV 
contrast is optional. Patient should empty his/her bladder immediately before the 
acquisition of images. For the emission scanning, the acquisition should be performed in 
2D or 3D mode in accordance with the manufacturer’s recommendations. The emission 


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55 
scan must be corrected for scatter, random events, and dead-time losses using the 
manufacturer’s recommended procedure. The image reconstruction will be performed 
using the manufacturer recommended parameters. Images should be attenuation corrected 
using CT data (note that if IV contrast is used, blood FDG SUV may be altered; therefore 
attenuation correction must be done without contrast).  
13.1.4 Response Criteria 
 
13.1.4.1 
Evaluation of Target Lesions  
Complete Response (CR): Disappearance of all target lesions.  Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to <10 mm.  
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters. 
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum 
if that is the smallest on study).  In addition to the relative increase of 20%, the sum 
must also demonstrate an absolute increase of at least 5 mm.  (Note:  the appearance of 
one or more new lesions is also considered progressions).  
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 
 
13.1.4.2 
Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions and normalization 
of tumor marker level.  All lymph nodes must be non-pathological in size (<10 mm 
short axis). 
Note:  If tumor markers are initially above the upper normal limit, they must normalize 
for a patient to be considered in complete clinical response.  
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or maintenance 
of tumor marker level above the normal limits. 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  Unequivocal progression should not 
normally trump target lesion status.  It must be representative of overall disease status 
change, not a single lesion increase.     


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Although a clear progression of “non-target” lesions only is exceptional, the opinion of 
the treating physician should prevail in such circumstances, and the progression status 
should be confirmed at a later time by the review panel (or Principal Investigator). 
 
13.1.4.3 
Evaluation of New Lesions  
The finding of a new lesion should be unequivocal (i.e. not due to difference in 
scanning technique, imaging modality, or findings thought to represent something 
other than tumor (for example, some ‘new’ bone lesions may be simply healing or flare 
of pre-existing lesions). However, a lesion identified on a follow-up scan in an 
anatomical location that was not scanned at baseline is considered new and will indicate 
PD. If a new lesion is equivocal (because of small size etc.), follow-up evaluation will 
clarify if it truly represents new disease and if PD is confirmed, progression should be 
declared using the date of the initial scan on which the lesion was discovered.  
 
13.1.4.4 
Evaluation of Best Overall Response  
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).  The patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria. 
For Participants with Measurable Disease (i.e., Target Disease)  
Target  
Lesions 
Non-Target  
Lesions 
New  
Lesions 
Overall  
Response 
Best Overall Response when  
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks Confirmation** 
CR 
Non-CR/NonPD No 
PR 
>4 wks Confirmation**  
CR 
Not evaluated 
No 
PR 
PR 
Non-
CR/NonPD/not 
evaluated 
No 
PR 
SD 
Non-
CR/NonPD/not 
evaluated 
No 
SD 
Documented at least once >4 
wks from baseline**  
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR  
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 


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57 
  
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**        Only for non-randomized trials with response as primary endpoint.  
***      In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
Note: Participants with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be reported 
as “symptomatic deterioration.” Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
 
 


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For Participants with Non-Measurable Disease (i.e., Non-Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
 ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised 
13.1.5 Duration of Response 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date 
that recurrent or progressive disease is objectively documented (taking as reference for 
progressive disease the smallest measurements recorded since the treatment started, or 
death due to any cause. Participants without events reported are censored at the last disease 
evaluation). 
Duration of overall complete response: The duration of overall CR is measured from the 
time measurement criteria are first met for CR until the first date that progressive disease 
is objectively documented, or death due to any cause. Participants without events reported 
are censored at the last disease evaluation. 
Duration of stable disease:  Stable disease is measured from the start of the treatment until 
the criteria for progression are met, taking as reference the smallest measurements recorded 
since the treatment started, including the baseline measurements.  
13.1.6 Progression-Free Survival 
Overall Survival: Overall Survival (OS) is defined as the time from randomization (or 
registration) to death due to any cause, or censored at date last known alive.  
Progression-Free Survival: Progression-Free Survival (PFS) is defined as the time from 
randomization (or registration) to the earlier of progression or death due to any cause. 
Participants alive without disease progression are censored at date of last disease 
evaluation.  
Time to Progression: Time to Progression (TTP) is defined as the time from randomization 
(or registration) to progression, or censored at date of last disease evaluation for those 
without progression reported.  
14. 
DATA REPORTING / REGULATORY REQUIREMENTS 


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14.1 
Data Reporting  
14.1.1 Method  
The QACT will collect, manage, and perform quality checks on the data for this study. 
14.2 
Data Safety Monitoring  
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity 
and accrual data from this study. The committee is composed of clinical specialists with experience 
in oncology and who have no direct relationship with the study. Information that raises any 
questions about participant safety will be addressed with the Overall PI and study team.  
The DSMC will review each protocol up to four times a year or more often if required to review 
toxicity and accrual data. Information to be provided to the committee may include: up-to-date 
participant accrual; current dose level information; DLT information; all grade 2 or higher 
unexpected adverse events that have been reported; summary of all deaths occurring with 30 days 
of intervention for Phase I or II protocols; for gene therapy protocols, summary of all deaths while 
being treated and during active follow-up; any response information; audit results, and a summary 
provided by the study team. Other information (e.g. scans, laboratory values) will be provided 
upon request.   
15. 
STATISTICAL CONSIDERATIONS 
15.1 
Study Design/Endpoints 
Phase I Component  
The MTD of MLN0128 will be determined using a standard 3+3 dose escalation design with three 
doses (3, 4, and 5 mg QD) and six patients treated at the proposed MTD. In the dose escalation 
design, 3 patients will be initially treated at the lowest dose level. If more than one patient 
experiences DLT at the lowest dose, the agent will be de-escalated to the 2 mg QD dose. If no 
DLT occurs in the first 3 patients at dose level 1, accrual to the next dose will begin, again with 3 
patients. If at any dose one DLT occurs in the first 3 patients, 3 additional patients will be treated 
at that dose level and the dose either escalated or deemed the MTD if none of the additional 3 
patients experiences DLT. If one or more of the additional 3 patients experiences DLT, the MTD 
will have been exceeded and the MTD will be defined to be the next lower dose. If at any time 2 
or more patients experience DLT at a dose level, the MTD will have been exceeded. Patients will 
be treated through the two cycles for DLT assessment. 
With this escalation strategy, the table below gives the probability of escalation as a function of 
the true underlying DLT rate for a variety of true rates. There will be 6 patients treated at the MTD 
before moving to the phase II component of the study. That is, if only 3 patients had been treated 
at the recommended dose, a second cohort of 3 patients will be added. The phase I component of 


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60 
this study will therefore accrue a potential total of 18 patients. See also section 7.3 for additional 
details on the dose escalation design, proposed dosing and definition of DLT.  
True rate of DLT 
10%  20%  30%  40%  
50%  60%  70% 
Probability of escalation 
.91 
.71 
.49 
.31 
.17 
.08 
.03 
Phase II Component  
The primary objective of this trial is to assess MLN0128 activity in patients with 
recurrent/metastatic MCC. MLN0128 will be considered an active drug for recurrent/metastatic 
MCC if there is evidence that the true objective response rate is at least 40% (against a null of 10% 
in this heterogeneous population). We will adopt a two-stage design in this study whereby at the 
first stage 6 patients are entered. If one or more responses are seen amongst the first 6 patients, an 
additional 10 treated patients will be entered. A total number of responses of 4 or more out of 16 
patients will be sufficient evidence to reject the null hypothesis. We will consider MLN0128 to be 
an active drug in this patient population.   
With this design, the probability of concluding the proposed treatment is promising is 0.91 if the 
true but unknown response rate is 40% (power) but 0.06 if the true disease control rate is 10% 
(type I error). The probability of stopping early under the null hypothesis is 53%. The operating 
characteristics of this design are calculated using the exact binomial distribution.  
Progression-free (PFS), disease control rate (DCR) and overall survival (OS) of patients receiving 
MLN0128 for MCC will be described using the method of Kaplan and Meier. Survival and 90% 
confidence intervals for OS and PFS will be reported, although the precision for these estimates is 
expected to be low given the small sample size, hence these analyses will be largely descriptive. 
Toxicity is an important secondary endpoint. Assuming the trial moves to the second stage, with 
16 treated patients there is at least 56% probability of observing one or more rare (5% true 
probability) events, and over 90% probability of observing toxicities that have a true occurrence 
of at least 14%. A 90% two-sided exact binomial confidence interval on any given adverse event 
rate will be no wider than 45 percentage points.  
Continuous Toxicity Monitoring:  Due to anticipated treatment-related toxicities, continuous 
monitoring of serious treatment-related toxicities will be performed. The study will be terminated 
early if excessive incidence of treatment related toxicity is observed. 
15.2 
Sample Size, Accrual Rate and Study Duration 
The planned sample size is 6-34 patients total. The anticipated annual accrual is approximately 6 
patients. The anticipated period of active accrual is expected to be 24-36 months depending upon 
the enrollment required for the phase I component.  
16. 
PUBLICATION PLAN 


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61 
The results should be made public within 24 months of reaching the end of the study. The end of 
the study is the time point at which the last data items are to be reported, or after the outcome data 
are sufficiently mature for analysis, as defined in the section on Sample Size, Accrual Rate and 
Study Duration. If a report is planned to be published in a peer-reviewed journal, then that initial 
release may be an abstract that meets the requirements of the International Committee of Medical 
Journal Editors. A full report of the outcomes should be made public no later than three (3) years 
after the end of the study. 
17. 
ADMINISTRATIVE REQUIREMENTS 
17.1 
Product Complaints 
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 Millennium (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 1-844-ONC-TKDA (1-844-662-8532) e-mail: 
GlobalOncologyMedinfo@takeda.com  
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 Millennium Pharmacovigilance (refer to Section 
14.2).  
18. 
REFERENCES 
1. Voog E, Biron P, Martin JP, et al. Chemotherapy for patients with locally-advanced or 
metastatic merkel cell carcinoma. Cancer 1999; 85(12):2589-2595.  
2. Shuda M, Kwun HJ, Feng H, et al. Human merkel cell polyomavirus small T antigen is an 
oncoprotein targeting 4E-BP1 translation regulator. J Clin Invest 2011; 121(9):3623-3634.  
3. Lin Z, McDermott A, Shao L, et al. Chronic mTOR activation promotes cell survival in 
Merkel cell carcinoma. Cancer Letters 2014; 344(2):272-281.  
4. Nardi V, Song Y,  Santamaria-Barria JA, et al. Activation of PI3K signaling in Merkel cell 
carcinoma. Clin Cancer Res 2012; 18(5):1227-1236.  
5. Schoffski P, Riggert S, Fumoleau P, et al. Phase I trial of intravenous aviscumine 
(rViscumin) in patients with solid tumors: a study of the European Organization for 
Research and Treatment of Cancer New Drug Development Group. Annals of Oncology 
2004: 15(12):1816-1824.  
6. O’Quigley J, Zohar S. Experimental designs for phase I and phase I/II dose-finding studies. 
British Journal of Cancer 2006: 94:609-613.   
7. Feng H, Shuda M, Chang Y, Moore PS. Clonal integration of a polyomavirus in human 
Merkel cell carcinoma. Science. 2008;319(5866):1096–1100.  


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62 
8. Richter JD, Sonenberg N. Regulation of cap-dependent translation by eIF4E inhibitory 
proteins. Nature. 2005;433(7025):477–480.   
9. Pause A, Belsham GJ, Gingras A-C et al. Insulin-dependent stimulation of protein 
synthesis 
by 
phosphorylation 
of 
a 
regulator 
of 
5’-cap 
function. 
Nature. 
1994;371(6500):762–767.  
10. Lazaris-Karatzas A, Montine KS, Sonenberg N. Malignant transformation by a eukaryotic 
initiation factor subunit that binds to mRNA 5’ cap. Nature. 1990;345(6275):544–547.  
11. Avdulov S, et al. Activation of translation complex eIF4F is essential for the genesis and 
maintenance of the malignant phenotype in human mammary epithelial cells. Cancer Cell. 
2004;5(6):553–563.  
 


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63 
APPENDIX A  
PERFORMANCE STATUS CRITERIA 
ECOG Performance Status Scale 
Karnofsky Performance Scale  
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to 
carry 
on 
all 
pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms,  
but  
ambulatory. 
Restricted in physically strenuous 
activity, but ambulatory and able to 
carry out work of a light or 
sedentary 
nature 
(e.g., 
light 
housework, office work).  
 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work.  
2 
In  
bed  <50%  of  the  
time. 
Ambulatory and capable of all 
selfcare, but unable to carry out any 
work activities.  Up and about more 
than 50% of waking hours. 
 
60 
Requires occasional assistance, but is 
able to care for most of his/her needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely 
disabled, 
hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely  
disabled.  Cannot carry on any 
selfcare.  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  
INFORMATION ON POSSIBLE DRUG INTERACTIONS 
MLN0128 is metabolized by CYP2C19, CYP3A4, and CYP2C9.  
There are no known strong specific CYP2C9 inhibitors or inducers. Examples of moderate 
inhibitors of CYP2C9 are fluconazole and miconazole; moderate inducers of CYP2C9 are 
carbamazepine and rifampin. These agents show some degree of overlap with their modulation of 
CYP3A4 and CYP2C19 activity and should hence be considered with similar caution.  
Strong inhibitors of CYP2C19 include fluconazole, fluvoxamine, omeprazole, and ticlopidine. 
Strong inhibitors of CYP3A4 include ketoconazole, itraconazole, ritonavir, mibefradil, indinavir, 
and clarithromycin. Strong inducers of CYP3A4 include phenobarbital, phenytoin, 
carbamazepine, St. John’s wort, and rifampin (also a moderate CYP2C19 inducer).  
Strong Inhibitors and Strong Inducers of CYP2C19, and CYPE3A4   
Strong CYP2C19 Inhibitors 
fluconazole 
fluvoxamine 
ticlopidine 
Moderate CYP3A4 Inhibitors 
amprenavir  
darunavir/ritonavir  
fosamprenavir  
aprepitant 
Diltiazem 
grapefruit juice(a) 
atazanavir 
erythromycin 
imatinib 
ciprofloxacin 
fluconazole  
verapamil 
Strong CYP3A4 Inhibitors 
boceprevir  
ketoconazole  
ritonavir  
clarithromycin 
lopinavir/ritonavir  
saquinavir  
conivaptan  
mibefradil(b) 
telaprevir 
grapefruit juice(a) 
nefazodone  
telithromycin 
indinavir 
Nelfinavir 
voriconazole 
itraconazole 
posaconazole  
Clinically Significant Enzyme Inducers 
carbamazepine 
Rifabutin 
St. Johns Wort 
phenobarbital  
Rifampin 
phenytoin  
rifapentine  
 
Note that these lists are not exhaustive.    


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(a) The effect of grapefruit juice varies widely among brands and is concentration-, dose-, and 
preparation-dependent.  Studies have shown that it can be classified as a “strong CYP3A 
inhibitor” when a certain preparation was used (eg, high dose, double strength) or as a 
“moderate CYP3A inhibitor” when another preparation was used (eg, low dose, single 
strength). 
(b) Withdrawn from the United States market because of safety reasons.  
Sources:  
ganfyd.org/index.php?title=Inhibitors_of_CYP3A4  and 
medicine.iupui.edu/clinpharm/ddis/