Clinical trial NCT03193853
Conditions: Triple Negative Breast Cancer
Sponsor: Joyce O'Shaughnessy
Start date: 2017-07-18; Completion date: 2022-12-01
Enrollment: 12 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study evaluates efficacy of TAK- 228 and TAK- 117 followed by cisplatin and nab paclitaxel in patients with metastatic triple negative breast cancer.

Detailed description:
Seventy to eighty percent of breast cancers have a gene expression profile which is characterized by homologous recombination deficiency (HRD) and high proliferation. HRD leads to errors in DNA pathway \[non -homologous end joining (NHEJ)\] that repair DNA-breaks, a process required for metastatic triple negative breast cancer (TNBC) survival. The hypothesis of this pilot trial is that administration of the oral combination of TAK-228 and TAK-117 (PIKTOR) will inhibit NHEJ in metastatic TNBC, leading at the time of disease progression to metastases that are HR-deficient and sensitive to cisplatin plus nab paclitaxel therapy.

Arms: arm 1: Patients with metastatic TNBC who meet the enrollment criteria will receive TAK-228 and TAK-117 until disease progression followed by nab paclitaxel plus cisplatin for six cycles. Patients who did not progress may continue nab paclitaxel under treating physicians discretion.
Interventions: intervention 1: Tak-228 & Tak-117 intervention 2: Cisplatin & Nab Paclitaxel
Intervention descriptions: intervention 1: Patients will receive 4mg oral TAK-228 and 200mg TAK-117 tablets until disease progression. intervention 2: following Tak-228 \& Tak-117 standard nab paclitaxel 175-220 mg/m2 plus cisplatin 60-75 mg/m2 infusion for six cycles. Patients who did not progress may continue nab paclitaxel under treating physicians discretion

Protocol documents:
Prot_SAP_000.pdf: 
PIKTOR (TAK-228 + TAK-117) 
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CLINICAL STUDY PROTOCOL  
Takeda X31026/Baylor 017-113 
 
Phase II Clinical Trial of Treatment with the oral combination of TAK-228 and TAK-
117 to inhibit homologous recombination (HR) followed by cisplatin and nab paclitaxel 
in patients with chemotherapy-pretreated metastatic triple negative breast cancer 
 
 
 
 
Indication: 
Metastatic breast cancer 
Phase: 
2 
 
 
 
Protocol History 
Original 
 
07 April 2017 
Amendment 1 
 
30 May 2017  
Amendment 2 
 
18 December 2017 
Amendment 3 
 
20 July 2018  
 
 
Investigator and Study Center: 
Joyce O'Shaughnessy, MD 
Baylor Scott and White Research Institute 
3410 Worth Street, Suite 400 
Dallas, TX 75246 
 
Phone: 214-370-1795 
 
 
 
 
 
 
 
 
This is an investigator-initiated study.  The principal investigator, Joyce O'Shaughnessy, 
MD, (who may also be referred to as the sponsor-investigator), is conducting the study and 
acting as the sponsor. Therefore, the legal/ethical obligations of the principal investigator 
include both those of a sponsor and those of an investigator. 


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PROTOCOL SUMMARY  
 
Study Title: Phase II clinical trial of treatment with the oral combination of TAK-228 and TAK-
117 to inhibit homologous recombination (HR) followed by cisplatin and nab paclitaxel in patients 
with chemotherapy-pretreated metastatic triple negative breast cancer 
Phase:  2 
Number of Patients:  10-20 
Study Objectives  
Primary 
• To assess the objective response rate associated with sequential treatment with the oral 
combination of TAK-228 and TAK-117 followed by cisplatin plus nab paclitaxel in 
metastatic triple negative breast cancer (metTNBC) patients. 
Secondary 
• To assess the safety of TAK-228 and TAK-117 followed by cisplatin plus nab paclitaxel in 
metTNBC pts. 
• To assess the duration of response to sequential treatment with the oral combination of 
TAK-228 and TAK-117 followed by cisplatin plus nab paclitaxel in metTNBC pts. 
• To assess the metastatic TNBC tissues for homologous recombination deficiency (HRD) 
by evaluating inactivating mutations in HR genes on Next Generation Sequencing (NGS) 
as well as by evaluating the overall and pattern-specific mutational load in the cancers on 
NGS.  
• To collect frozen and/or formalin-fixed paraffin embedded (FFPE) tissue for biomarker 
development. 
Overview of Study Design:   
Seventy to 80% of breast cancers have a basal gene expression profile which is characterized by 
homologous recombination deficiency (HRD) and high proliferation. HRD leads to upregulation 
of the activity of the non-homologous end joining (NHEJ) error-prone pathway that repairs DNA 
double strand breaks, a process required for TNBC survival. The hypothesis of this Phase II trial is 
that administration of the oral combination of TAK-228 and TAK-117 (PIKTOR) will inhibit 
NHEJ in metastatic triple-negative breast cancer (TNBC), leading at the time of disease 
progression to metastases that are HR-deficient and sensitive to cisplatin plus nab paclitaxel 
therapy. A patient with an exceptional complete and durable response of her primary-refractory 
metastatic TNBC with PI3K pathway inhibition followed at disease progression by nab 
paclitaxel/cisplatin provides the rationale for a prospective trial of PIKTOR followed by the 
cisplatin/nab paclitaxel regimen in pretreated metastatic TNBC patients.  
Patients will receive PIKTOR until PD, followed by nab paclitaxel plus cisplatin for 6 cycles. 
Patients will undergo core needle biopsies of metastatic locoregional or pulmonary or hepatic 
disease prior to the start of PIKTOR treatment, and at the time of disease progression on PIKTOR 
(prior to beginning nab paclitaxel plus cisplatin) for NGS and biomarker development.  


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Patients who have residual locally recurrent or metastatic disease upon completion of nab 
paclitaxel/cisplatin may be treated with standard of care breast cancer therapies off study, at the 
recommendation of the treating physician. 
Study Population:   
Androgen receptor-negative, metastatic triple negative breast cancer patients who have not 
received more than 3 prior chemotherapy regimens for metastatic disease. 
Duration of Study:   
The duration of patient participation in the study will be a maximum of 18 months.  
 
 


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STUDY OVERVIEW DIAGRAM 
 
 
 


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TABLE OF CONTENTS 
PROTOCOL SUMMARY ........................................................................................................2 
STUDY OVERVIEW DIAGRAM ...........................................................................................4 
LIST OF TABLES AND FIGURES ........................................................................................8 
LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS ..............................................9 
1. INTRODUCTION ..............................................................................................................13 
1.1 Background on Triple Negative Breast Cancer ............................................................13 
1.2 Homologous Recombination Deficiency in Breast Cancer ..........................................13 
1.3 PIKTOR (TAK-228 + TAK-117) .................................................................................14 
1.3.1 TAK-228 ................................................................................................................14 
1.3.2 TAK-117 ................................................................................................................14 
1.4 Nab-Paclitaxel in MBC ................................................................................................14 
1.5 Nab-Paclitaxel plus Cisplatin in MBC .........................................................................15 
1.6 Nab paclitaxel plus Carboplatin in Metastatic TNBC ..................................................16 
1.7 Exceptional Responder Clinical History and Tumor Molecular Alterations ...............16 
2. SUMMARY OF NONCLINICAL EXPERIENCE ............................................................18 
2.1 TAK-228 18 
2.2 Nonclinical Experience with TAK117 .........................................................................19 
2.3 TAK-228 in Combination with TAK-117 (PIKTOR) ..................................................19 
3. SUMMARY OF CLINICAL EXPERIENCE ....................................................................20 
3.1 Clinical Experience with TAK-228 ..............................................................................20 
3.2 Clinical Experience with TAK-117 ..............................................................................22 
3.3 Clinical Experience with TAK-228 + TAK-117 (PIKTOR; study C32001) ................24 
3.3.1 Pharmacokinetics ...................................................................................................24 
3.3.2 Pharmacodynamics ................................................................................................24 
3.3.3 Safety .....................................................................................................................24 
3.3.4 Potential Risks .......................................................................................................25 
4. SPECIAL WARNINGS AND PRECAUTIONS ...............................................................26 
4.1 Insulin and Glucose Levels ...........................................................................................26 
4.2 Cardiac Effects .............................................................................................................26 
4.3 Renal Function ..............................................................................................................26 
4.4 Rash 
27 
4.5 Pneumonitis ..................................................................................................................27 
4.6 Interactions with other Medicines and other Forms of Interactions .............................27 
5. RATIONALE FOR THE RP2D FOR PIKTOR (TAK-228 + TAK-117) ..........................27 
6. STUDY RATIONALE .......................................................................................................28 
7. STUDY OBJECTIVES ......................................................................................................28 
7.1 Primary Objectives .......................................................................................................28 
7.2 Secondary Objectives ...................................................................................................28 
8. STUDY ENDPOINTS ........................................................................................................29 
8.1 Primary Endpoints ........................................................................................................29 
8.2 Secondary Endpoints ....................................................................................................29 
9. STUDY DESIGN ...............................................................................................................29 
9.1 Overview of Study Design ...........................................................................................29 
9.2 Number of Patients .......................................................................................................30 


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9.3 Duration of Study .........................................................................................................30 
10. STUDY POPULATION ...................................................................................................30 
10.1 Inclusion Criteria ........................................................................................................30 
10.2 Exclusion Criteria .......................................................................................................31 
11. STUDY TREATMENT ADMINISTRATION ................................................................33 
11.1 PIKTOR Administration .............................................................................................34 
11.2 Chemotherapy Administration ...................................................................................35 
11.3 TAK-228 Dose-Modification Guidelines ...................................................................35 
11.3.1 Criteria for Dose Interruption during a PIKTOR Cycle ......................................35 
11.3.2 Criteria for Discontinuation of PIKTOR .............................................................36 
11.3.3 Dose Modifications for Chemotherapy Treatment Associated Toxicity .............36 
11.4 Chemotherapy Treatment Delay or Discontinuation ..................................................37 
11.5 Schedule of Assessments ............................................................................................37 
11.5.1 Prestudy Assessments ..........................................................................................37 
11.5.2 Registration Procedures .......................................................................................38 
11.5.3 Assessments During Treatment ...........................................................................39 
11.5.4 Off Treatment/End of Treatment Assessments ....................................................41 
11.5.5 Follow Up Assessments .......................................................................................42 
11.5.6 Unscheduled Visits ..............................................................................................42 
11.5.7 Blood Samples for Exome Sequencing ...............................................................42 
11.5.8 Biopsies ................................................................................................................43 
11.6 Excluded Concomitant Medications and Procedures .................................................43 
11.7 Permitted Concomitant Medications and Procedures .................................................44 
11.8 Precautions and Restrictions .......................................................................................45 
11.9 Management of Clinical Events .................................................................................46 
11.9.1 Management of Hyperglycemia...........................................................................46 
11.9.2 Management of Hyperlipidemia ..........................................................................48 
11.9.3 Management of Oral Mucositis ...........................................................................48 
11.9.4 Management of Rash ...........................................................................................49 
11.9.5 Management of Nausea/Vomiting .......................................................................50 
11.9.6 Management of Cardiac Abnormalities ...............................................................51 
11.9.7 Management of Patients with QTc Prolongation .................................................51 
11.9.8 Management of Asthenia, Weakness and Fatigue ...............................................52 
11.9.9 Management of Aspartate Aminotransferase/Alanine Aminotransferase 
Elevations .......................................................................................................53 
11.9.10 Management of Non-infectious Pneumonitis ....................................................53 
11.10 Description of Investigational Agents ......................................................................54 
11.11 Preparation, Reconstitution, and Dispensing ............................................................55 
11.12 Packaging and Labeling ............................................................................................55 
11.13 Storage, Handling, and Accountability .....................................................................55 
11.14 Study Compliance .....................................................................................................55 
11.15 Termination of Treatment and/or Study Participation ..............................................56 
12. EFFICACY ASSESSMENTS (SOLID TUMOR) ...........................................................57 
12.1 Response Criteria ........................................................................................................57 
13. STATISTICAL AND QUANTITATIVE ANALYSES ...................................................57 
13.1 Statistical Methods .....................................................................................................57 


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13.1.1 Determination of Sample Size .............................................................................57 
13.1.2 Populations for Analysis ......................................................................................57 
13.1.3 Patient Characteristics and Disposition ...............................................................58 
13.1.4 Hypothesis and Endpoints ...................................................................................58 
13.1.5 Biopsies ................................................................................................................58 
14. ADVERSE EVENTS........................................................................................................58 
14.1 Definitions ..................................................................................................................58 
14.1.1 Adverse Event Definition ....................................................................................58 
14.1.2 Adverse Drug Reaction ........................................................................................59 
14.1.3 Serious Adverse Event Definition .......................................................................59 
14.2 Procedures for Reporting Serious Adverse Events .....................................................60 
14.3 Procedures for Reporting Drug Exposure During Pregnancy and Birth Events ........62 
15. ADMINISTRATIVE REQUIREMENTS ........................................................................62 
15.1 Product Complaints ....................................................................................................62 
16. REFERENCES .................................................................................................................63 
17. 
APPENDICES ............................................................................................................67 
Appendix I: Eastern Cooperative Oncology Group (ECOG) Scale for Performance 
Status............................................................................................................67 
Appendix II: Cockcroft-Gault Equation .............................................................................68 
Appendix III: New York Heart Association Classification of Cardiac Disease .................69 
Appendix IV: List of Relevant Cytochrome P450 Inhibitors and Inducers .......................70 
Appendix V: NCI Common Terminology Criteria for Adverse Events (CTCAE), 
Version 4.0 ...................................................................................................71 
Appendix VI: Schedule of Assessments .............................................................................72 
Appendix VII: Research Biopsies ......................................................................................74 
Appendix VIII: Patient Diaries for PIKTOR administration ..............................................82 
Appendix IX: Patient Diaries for glucometer readings ......................................................85 
 


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LIST OF TABLES and FIGURES 
Tables 
Table 1. 
Summary of TAK-228 Clinical Studies .........................................................21 
Table 2. 
Summary of TAK-117 Clinical Studies .........................................................23 
Table 3. 
Study C32001 Treatment Schema PIKTOR Dose Limiting Toxicity ............28 
Table 4. 
Treatment schema ...........................................................................................34 
Table 5. 
Dose Reduction Schedule for TAK-228 and TAK-117 .................................36 
Table 6. 
Management of Hyperglycemia .....................................................................47 
Table 7. 
Management of Hyperlipidemia .....................................................................48 
Table 8. 
Management of Oral Mucositis ......................................................................49 
Table 9. 
Management of Rash ......................................................................................49 
Table 10. 
Management of Nausea/Vomiting ..................................................................50 
Table 11. 
Management of Left Ventricular Dysfunction ...............................................51 
Table 12. 
Management of QTc Prolongation .................................................................51 
Table 13. 
Management of Asthenia, Weakness, and Fatigue .........................................52 
Table 14. 
Management of Aspartate Aminotransferase/Alanine Aminotransferase 
Elevations .......................................................................................................53 
Table 15. 
Management of Non-infectious Pneumonitis .................................................54 
 
 


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LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS 
Common abbreviations used in oncology protocols are provided below.  Program-specific 
or protocol-specific abbreviations must be added to this list, and unnecessary abbreviations 
removed, as applicable.  Abbreviations that are retained should not be changed.  
Abbreviation 
Term 
AE 
adverse event 
AKT 
Protein kinase B 
ALP/ SGPT 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
API 
active pharmaceutical ingredient 
ASCO 
American Society of Clinical Oncologists 
AST/ SGOT 
aspartate aminotransferase 
BC 
Breast cancer 
BCRP 
breast cancer resistance protein 
BID 
bis in die; twice a day 
BSWRI 
Baylor Scott & White Research Institute 
CBC 
complete blood count 
CL 
clearance, IV dosing 
CNS 
central nervous system 
CO2 
carbon dioxide 
CR 
complete response    
CRF 
Case report form 
CRM 
continual reassessment method 
CV 
cardiovascular  
DLT 
dose-limiting toxicity 
DNA 
deoxyribonucleic acid 
EC 
ethics committee 
ECG 
electrocardiogram; electrocardiography 
ECHO 
echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EGFR 
Epidermal Growth Factor Receptor 
EOS 
End of Study (visit) 
EOT 
End of Treatment (visit) 


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Abbreviation 
Term 
EU 
European Union 
FDA 
United States Food and Drug Administration 
FSG 
Fasting serum glucose 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practice 
Hb 
Hemoglobin 
HbA1c 
Glycosylated hemoglobin 
Hct 
Hematocrit 
HDPE 
high-density polyethylene 
hERG 
human ether-à-go-go related gene 
HIV 
human immunodeficiency virus 
HR 
Homologous recombination 
HRD 
Homologous recombination deficiency 
IB 
Investigator’s Brochure 
IC50 
concentration producing 50% inhibition 
ICF 
informed consent form 
IEC 
independent ethics committee 
IGFR 
Insulin-like growth factor receptor 
IHC 
Immunohistochemistry 
IM 
Internal mammary 
IRB 
institutional review board 
IV 
intravenous; intravenously 
IVRS 
interactive voice response system 
Ki 
inhibition constant 
LDH 
lactate dehydrogenase 
LFT 
liver function test(s) 
LLN 
Lower limit normal 
LN 
Lymph node 
LVEF 
Left ventricular ejection fraction 
MBC 
Metastatic breast cancer 
MedDRA 
Medical Dictionary for Regulatory Activities 
metTNBC 
Metastatic triple negative breast cancer 


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Abbreviation 
Term 
MM 
multiple myeloma 
MOA 
mechanism of action 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
mTOR 
mechanistic target of rapamycin 
mTOR[1] or [2] 
target of rapamycin complex [1 or 2] 
MUGA 
multiple gated acquisition (scan) 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for 
Adverse Events 
NGS 
Next generation sequencing 
NHEJ 
Non-homologous end-joining 
NHL 
non-Hodgkin lymphoma 
nM 
Nanomolar 
NPO 
nothing by mouth 
NYHA 
New York Heart Association 
OTC 
Over the counter 
PD 
progressive disease (disease progression) 
PGx 
Pharmacogenomic(s) 
PIKTOR 
TAK-228 + TAK-117 combination 
PK 
pharmacokinetic(s) 
PO 
per os; by mouth (orally) 
PPI 
Proton pump inhibitor 
PR 
partial remission or partial response choose one 
PRO 
patient-reported outcome 
PSA 
prostate-specific antigen 
QD 
quaque die; each day; once daily 
QID 
quarter in die; 4 times a day 
QOD 
quaque altera die; every other day 
QOL 
quality of life 
QTc 
rate-corrected QT interval (millisec) of electrocardiograph 
QW 
Once per week 
RBC 
red blood cell 
RECIST 
Response Evaluation Criteria in Solid Tumors 


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Abbreviation 
Term 
RP2D 
Recommended phase 2 dose 
RPPA 
Reverse phase protein array 
SAE 
serious adverse event 
SC 
Subcutaneous 
SD 
stable disease 
TEAE 
Treatment emergent adverse event 
TGI 
tumor growth inhibition 
TIA 
Transient ischemic attack 
Tmax 
single-dose time to reach maximum (peak) concentration 
TNBC 
Triple negative breast cancer 
TPN 
Total parental nutrition 
TTP 
Time to progression 
UK 
United Kingdom 
ULN 
upper limit of the normal range 
US 
United States 
Vz 
volume of distribution in the terminal phase 
WBC 
white blood cell 
WM 
Waldenström macroglobunemia 
 
 
 


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1. INTRODUCTION 
1.1 Background on Triple Negative Breast Cancer 
Breast cancer is the most common malignancy in women worldwide, with incidence rates as 
high as 89.7 per 100,000 women.(1) Although there have been a number of important 
treatment advances in recent years, and overall mortality is declining due to earlier detection 
and more effective treatment of early stage disease, metastatic breast cancer (MBC) remains 
incurable and is the second leading cause of cancer deaths among women.(2) 
Triple-negative breast cancer (TNBC) is defined by the absence of ER, PgR, and HER2 
receptor expression. By hierarchical clustering of gene expression patterns, these cancers 
most often segregate with the “basal-like” intrinsic subtype.(3) Compared with other breast 
cancer subtypes, TNBC is associated with a worse prognosis, including a shorter time to 
recurrence in early-stage disease, and a shorter time between recurrence and death in the 
metastatic setting.(4) Because currently available targeted therapies such as endocrine or 
HER2-targeted agents are ineffective against this breast cancer subtype, treatment options 
for TNBC are limited to chemotherapy at this time. To date, no clear molecular target has 
been identified and proven to have therapeutic value. 
1.2 Homologous Recombination Deficiency in Breast Cancer 
Seventy to 80% of breast cancers have a basal gene expression profile which is 
characterized by homologous recombination deficiency (HRD) and high proliferation.(5) 
HRD leads to upregulation of the activity of the non-homologous end joining (NHEJ) error-
prone pathway that repairs DNA double strand breaks, a process required for TNBC 
survival.(6) A key nuclear enzyme that orchestrates NHEJ is DNA-Dependent Protein 
Kinase catalytic subunit (DNA-PKcs), a member of the PI3K super-family.(7) 
Nuclear Epidermal Growth Factor Receptor (EGFR) is activated by phospho-AKT and both 
nuclear EGFR and nuclear AKT phosphorylate and activate DNA-PK to promote NHEJ-
mediated repair of DNA double-strand breaks.(8) Loss of HR proficiency, which occurs in 
most TNBCs (the basal-like TNBCs), leads to increased EGFR expression in mammary 
epithelial cells.(9) However, it is not known whether activated, nuclear EGFR T564 and 
nuclear AKT that phosphorylate DNA-PK are increased in the setting of HRD in 
chemotherapy-resistant TNBC. 
BEZ-235 is a potent inhibitor of DNA-PKcs, as well as PI3K and TORC1/2, which inhibits 
NHEJ-mediated DNA double strand break repair, sensitizing cancers to DNA damaging 
agents.(10)  A phase I trials of the sachet formulation of BEZ-235 demonstrated that BEZ-
235 was safe with manageable toxicities( including mild to moderate fatigue, nausea, 
diarrhea, hyperglycemia, stomatitis and anemia) and had demonstrated antitumor activity 
against breast cancer.(11) However, although the mechanisms behind its activity were 
compelling, clinical development of this agent was stopped because of highly unpredictable 
intrapatient bioavailability that could not be overcome with various formulations (Novartis 
Oncology, personal communication, October, 2015). 
Another mechanism which inhibits DNA repair response is the dual inhibition of 
mTORC1/2. In preclinical studies, the dual inhibition of mTORC1 and mTORC2 decreased 


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DNA repair response as well as decreased the activity of AKT. This dual inhibition allowed 
for the partial re-sensitization of platinum-resistant ovarian cancer cells both in vitro and in 
vivo to platinum chemotherapy, as compared to single inhibition of mTORC1.(12) Blockade 
of the mTOR complexes may be a novel strategy to sensitize cancers to DNA damaging 
agents. 
1.3    PIKTOR (TAK-228 + TAK-117)  
1.3.1 TAK-228 
Millennium has developed TAK-228 (formerly INK128 and MLN0128), 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). TAK-
228 targets 2 distinct mTOR complexes, mTORC1 and mTORC2. 
In oncology, TAK-228 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. 
1.3.2 TAK-117 
TAK-117 (formerly MLN1117/INK1117) is an investigational, orally (PO) available, 
selective small molecule inhibitor of the Class I phosphoinositide 3-kinase (PI3K) alpha 
isoform (PI3Kα). 
Pharmacological data obtained to date suggest that TAK-117 may have therapeutic potential 
as an orally administered PI3Kα inhibitor for the treatment of cancers associated with 
dysregulated activation of the PI3K pathway such as breast, lung, endometrial, colon, 
gastroesophageal, gastric, and bladder cancers, among others. 
TAK-117 is being developed for the treatment of advanced solid tumors, both as a single 
agent and in combination with chemotherapy, such as paclitaxel and docetaxel, or other 
targeted therapies such as the investigational agents MLN8237 (alisertib) and TAK-659. 
TAK-117 is also being investigated in combination with the investigational agent TAK-228 
Together, the combination is referred to as PIKTOR. 
1.4 Nab-Paclitaxel in MBC 
In a phase I study, the MTD of nab-paclitaxel was determined to be 300 mg/m2 by 
30 minute infusion Q3W, without premedication or G-CSF support.(13) No severe 
hypersensitivity reactions occurred with nab-paclitaxel despite the absence of 
premedication. Dose-limiting toxicities included sensory neuropathy, stomatitis, and 
superficial keratopathy, which occurred at a dose of 375 mg/m2. 
Two multicenter phase II studies have evaluated 2 dose levels of nab-paclitaxel (300 mg/m2, 
n=63, and 175 mg/m2, n=43) in patients with metastatic breast cancer.(14,15) The ORRs in 
these 2 phase II trials were 40% (95% CI 25-54%) for the 175 mg/m2 dose, and 48% (95% 
CI 35-60%) for the 300 mg/m2 dose. Of 39 patients receiving 300 mg/m2 as first-line 
therapy for metastatic breast cancer, 64% (95% CI 49-79%) responded. This was contrasted 


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with a 45% response rate in similar patients at the lower dose level. Grade 4 neutropenia was 
noted in 24% of patients at the higher dose level, occurred primarily during the first cycle 
and resolved rapidly. 
 
A Phase III trial in patients with metastatic breast cancer compared nab-paclitaxel 
260 mg/m2 (n=229) to solvent-based paclitaxel 175 mg/m2 (n=225) given Q3W.(16) 
Efficacy analyses were based on the intent-to-treat (ITT) population. The ORR was 
significantly greater for nab-paclitaxel than for paclitaxel for all patients (33% v 19%, 
respectively; P = 0.001), patients who received first-line therapy (42% v 27%, respectively; 
P = 0.029), patients who received second-line or greater therapy (27% v 13%, respectively; 
P = 0.006), and patients who had received prior anthracycline therapy in either the 
adjuvant/metastatic setting (34% v 18%, respectively; P = 0.002) or the metastatic setting 
only (27% v 14%, respectively; P = 0.010). Tumor response rate was also significantly 
higher for nab-paclitaxel than for paclitaxel in patients with visceral dominant lesions (34% 
v 19%, respectively; P = 0.002) and in patients aged younger than 65 years (34% v 19%, 
respectively; P < 0.001). ORR also was greater for nab-paclitaxel compared with standard 
paclitaxel in patients with nonvisceral dominant lesions (34% v 19%, respectively) and in 
patients ≥ 65 years old (27% v 19%, respectively), but the results did not reach statistical 
significance because of the small number of patients in these subsets. 
Median time to progression (TTP) was significantly longer with nab-paclitaxel than with 
paclitaxel for all patients (23.0 v 16.9 weeks, respectively; hazard ratio [HR] = 0.75; P = 
0.006). There was a trend for greater median survival for all patients treated with nab-
paclitaxel than with paclitaxel (65.0 v 55.7 weeks, respectively; P = 0.374). Although no 
difference in survival was observed in first-line patients, the difference was statistically 
significant in patients who received nab- paclitaxel, compared with paclitaxel, as second-line 
or greater therapy (56.4 v 46.7 weeks, respectively; HR = 0.73; P = .024).(16) 
As expected with a higher dose of paclitaxel, treatment-related grade 3 sensory neuropathy 
occurred more frequently in the nab-paclitaxel arm than in the solvent-based paclitaxel arm 
(10% v 2%, respectively; P <  0.001); however, these episodes improved with interruption of 
treatment to grade 2 or 1 in a median 22 days and were easily managed with treatment 
interruption and dose reduction. By day 28 after its first occurrence, the number of patients 
with persistent grade 3 sensory neuropathy was the same (n = 4) in both study arms. No 
episodes of motor neuropathy or grade 4 sensory neuropathy were reported in either group. 
1.5 Nab-Paclitaxel plus Cisplatin in MBC 
The combination of nab-paclitaxel plus cisplatin was evaluated in a phase II study in 
73 patients with MBC.(17) nab-Paclitaxel was administered at a dosage of 125 mg/m2 IV on 
days 1, 8 and 15, together with cisplatin 75 mg/m2 IV on day 1, of an every-28-day cycle, 
for a maximum of 6 cycles. The ORR was 67% in all evaluable patients and 81% for 
patients receiving first-line treatment. Median PFS was 9.8 months, and median OS was 
26.9 months, demonstrating that the efficacy of nab-paclitaxel can be improved by the 
addition of cisplatin. Grade 4 neutropenia was reported in 63% of patients, with a 12% 
incidence of febrile neutropenia. Grade 3 peripheral neuropathy occurred in 26% of patients, 
and was cumulative and dose-limiting. 


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1.6 Nab paclitaxel plus Carboplatin in Metastatic TNBC 
The combination of nab paclitaxel (nab pac) and carboplatin (carbo) was evaluated in a 
phase II study in 191 patients with metastatic TNBC. Nab pac plus carbo reduced the risk of 
progression or death by 40% as compared to 2 other chemotherapy regimens (nab 
pac/gemcitabine (gem) and gem/carbo), according to results from the tnAcity study 
presented at the 2016 San Antonio Breast Cancer Symposium.(18) The median progression-
free survival (PFS) was 7.4 months with nab pac/carbo as compared to 5.4 months for nab 
pac/gem and 6 months for gem/carbo. The overall response rate (ORR) of nab pac/carbo was 
72%, while the ORR for nab pac/gem was 39% and 44% with gem/carbo.  
Based on these data, de novo metastatic TNBC patients are eligible for this study (PIKTOR 
followed by nab paclitaxel plus cisplatin) due to the high degree of effectiveness of this 
combination chemotherapy regimen as first-line therapy. 
1.7 Exceptional Responder Clinical History and Tumor Molecular Alterations 
The following description of the clinical and molecular tumor characteristics of a metastatic 
TNBC exceptional responder patient (19) provides the clinical rationale for conducting the 
proposed prospective pilot clinical trial of the oral combination of TAK-228 and TAK-117, 
followed by cisplatin and nab paclitaxel: 
At age 58 in 2006, the patient had a T1c 1+ node TNBC (denoted below: “Jul 2006 pre-
BEZ-235 Primary BC”) that was treated with adjuvant 5-fluorouracil, epirubicin, 
cyclophosphamide plus docetaxel (FEC/T) in addition to lumpectomy and breast 
radiotherapy. The patient has no family history of BC. 
Between 2008 and 2011 she had 4 locoregional recurrences in her axilla, supraclavicular 
(SC) fossa and internal mammary (IM) LNs treated unsuccessfully with surgery, radiation, 
and multiple cytotoxic agents including carboplatin. 
In February 2011, following an SC LN biopsy (denoted below: “Feb 2011 pre-BEZ-235 SC 
LN”), she was treated on a clinical trial with single agent BEZ-235, a PI3K/mTOR, ATM, 
ATR, and DNA-PKcs inhibitor, and had a partial response of 3 months duration, which was 
her first response to systemic therapy. The tempo of her disease changed following BEZ-235 
in that the SC LN that had been biopsied in Feb 2011 grew very rapidly at disease 
progression; this disease was resected in October 2011 (denoted below: “Oct 2011 post-
BEZ-235 SC LN”). She subsequently developed very rapidly enlarging IM LNs in 
November 2012, which pushed her sternum anteriorly (denoted below: “Nov 2012 post-
BEZ-235 IM LN”). 
In January 2013, she began treatment with 6 cycles of nab paclitaxel and cisplatin and 
developed a durable complete response (CR) that has been ongoing for 3.5 years. 
The pre-BEZ-235 SC LN tissue from February, 2011 that was highly chemotherapy- and 
radiation-refractory showed very strong EGFR signaling on RPPA (Figure 1). The nuclear 
phospho-EGFR T564 moiety was overexpressed in the patient’s pre-BEZ-235 
chemotherapy-refractory February 2011 SC LN (Figure 2). Following treatment with BEZ-
235, when the IM lymph node disease was very rapidly progressing in November 2012, 


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RPPA analysis on this tissue showed that EGFR and p-EGFR expression were not detectable 
(Figure 1).    
 
 
 
 
 
 
 
 
 
 
 
All of the patient’s longitudinal tissues that underwent NGS revealed a deletion of the 
SMARCA4 (BRG1) gene which is essential for normal HR proficiency.(20, 21) However, the 
Myriad HRD score on her primary breast cancer from 2006 was low, demonstrating non-
deficient HR, suggesting that the alternative DNA double strand repair mechanism, NHEJ, 
was functional in her primary breast cancer. The patient’s TNBC HRD score changed from 
HR non-deficient in her primary BC to HR-deficient following BEZ-235 treatment possibly 
due to inhibition of the PI3K/AKT pathway that drives NHEJ by BEZ-235, which amplified 
her cancer’s intrinsic HRD that was due to the SMARCA4 deletion. The November 2012 
rapidly progressive metastatic TNBC that had a high HRD score responded completely to 
cisplatin/nab paclitaxel chemotherapy.  
In this metastatic TNBC patient, the high EGFR expression and PI3K pathway activation 
observed on RPPA in her cancer pre-BEZ-235 switched to loss of EGFR and PI3K 
Tissues Analyzed
Her2
pHer2 
Y1248
Her1
pHer1 
Y1068
Her3
pHer3 
Y1289
pAkt 
S473
pmTOR 
S2448
Ribo. 
Prot. 
S235-236
p4E. BP1 
S65
pMek 1/2 
S217-221
pErk 1/2 
T202 
Y204
pJak 2 
Y1007-
1008
pStat3 
Y705
AR
pAR
Population mean
0.100
0.265
0.096
0.370
0.259
0.232
0.299
0.233
0.319
0.223
0.151
0.258
0.301
0.316
0.201
0.138
Plus 1 SD
0.228
0.404
0.194
0.519
0.367
0.375
0.503
0.375
0.497
0.377
0.281
0.470
0.441
0.446
0.383
0.292
Plus 2 SD
0.356
0.543
0.292
0.701
0.475
0.526
0.683
0.517
0.678
0.538
0.411
0.649
0.581
0.577
0.566
0.445
Jul 2006 pre-BEZ-235 Primary BC
0.015
0.119
0.083
0.269
0.270
0.014
0.030
0.297
0.465
0.180
0.102
0.084
0.290
0.311
0.016
0.095
Feb 2011 pre-BEZ-235 SC LN
0.030
0.243
0.196
0.485
0.391
0.446
0.149
0.159
0.418
0.385
0.224
0.271
0.268
0.388
0.092
0.103
Oct 2011 post-BEZ-235 SC LN
0.116
0.184
0.116
0.525
0.381
0.187
0.069
0.188
0.145
0.301
0.190
0.117
0.482
0.490
0.054
0.098
Nov 2012 post-BEZ-235 IM LN
0.043
0.179
0.075
0.274
0.335
0.335
0.072
0.215
0.173
0.106
0.296
0.098
0.071
0.202
0.045
0.087
Green = at the mean; yellow = between mean and 1 standard deviation (SD) from the mean; orange = increased between 1 SD and 2 SD from the mean; red = increased over 2 SD from the mean.
Tissues Analyzed
Histone 
H2AX S139
P90 RSK 
S380
CREB 
S133
EGFR T564 
(nuclear)
Population mean
0.410
1.605
2.279
9.858
Plus 1 SD
0.611
2.669
3.259
16.146
Plus 2 SD
0.812
3.733
4.239
22.434
Jul 2006 pre-BEZ-235 Primary BC
ND
1.216
2.145
ND
Feb 2011 pre-BEZ-235 SC LN
ND
ND
ND
17.527
Oct 2011 post-BEZ-235 SC LN
ND
1.430
2.307
ND
Nov 2012 post-BEZ-235 IM LN
0.535
ND
ND
ND
Note: population is not established, therefore these are considered preliminary results 
(denoted with shaded colors).
Green = at the mean; yellow = between mean and 1 standard deviation (SD) from the mean; 
orange = increased between 1 SD and 2 SD from the mean; red = increased over 2 SD from 
the mean; gray=not done.
FIGURE 1 
FIGURE 2 


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activation and increased MAPK pathway activation in the November 2012 tissue post-BEZ-
235 (Figure 1). Of note, this switch from PI3K to MAPK pathway activation, with a 
concomitant substantial increase in HRD (as measured by H2AX overexpression) is 
precisely what was observed in the seminal work by Juvekar, Baselga and Cantley when the 
active PI3K pathway was inhibited by buparlisib in preclinical TNBC models.(22) 
The above patient’s exceptional complete and durable response of her primary-refractory 
metastatic TNBC with PI3K pathway inhibition followed at disease progression by nab 
paclitaxel/cisplatin provides the rationale for a prospective trial of PIKTOR followed by the 
cisplatin/nab paclitaxel regimen in pretreated metastatic triple negative breast cancer 
patients.  
2.    SUMMARY OF NONCLINICAL EXPERIENCE 
2.1 TAK-228 
The mammalian mTOR serine/threonine kinase has a central role in regulating cellular 
growth and metabolism in response to external environmental factors.(23, 24) The mTOR 
kinase binds with other proteins to form 2 distinct multiprotein complexes, TORC1 and 
TORC2. The TORC1 complex is stimulated by growth factors and amino acids and 
regulates cell growth by controlling the activity of the ribosomal protein S6 kinase (S6K) 
and eukaryotic initiation factor 4-binding protein (4E-BP1).(25) The TORC2 complex is 
activated by growth factors and promotes cell survival, proliferation, and actin cytoskeleton 
organization by phosphorylating and activating kinases, such as serine/threonine-specific 
protein kinase (AKT) kinase (also known as protein kinase B), which is a regulator of 
apoptosis.(26, 27) 
Two major classes of mTOR inhibitors are under development, allosteric inhibitors and 
ATP-competitive inhibitors. The first-generation, or allosteric, inhibitors include rapamycin 
and the related analogs or rapalogs temsirolimus, everolimus, and ridaforolimus. The 
rapalogs effectively inhibit phosphorylation of S6K but only partially inhibit the 
phosphorylation of 4E-BP1, which regulates cap-dependent translation of transcripts for cell 
survival, proliferation, and angiogenesis.(24) Thus, rapamycin and the rapalogs are only 
partial inhibitors of TORC1.(24) 
The ATP-competitive inhibitors, such as TAK-228, bind to the catalytic domain of mTOR 
and thus inhibit both TORC1 and TORC2 complexes, including the rapamycin-insensitive 
or resistant actions of TORC1, such as phosphorylation of 4E-BP1.(28-30) 
The rapalogs temsirolimus and everolimus have been approved by the US Food and Drug 
Administration (FDA) as monotherapy for patients with advanced renal cell carcinoma 
(temsirolimus and everolimus), advanced pancreatic neuroendocrine tumors (everolimus), 
and subependymal giant cell astrocytoma associated with tuberous sclerosis (everolimus). 
However, resistance to single-agent rapalog therapy occurs and may be related to either 
incomplete inhibition of the targeted pathway or loss of S6K-mediated feedback inhibition 
of growth factor receptor signaling leading to paradoxical hyperactive signaling. The normal 
feedback loop involves activated S6K, which phosphorylates and inactivates insulin receptor 
substrate-1 and inhibits signaling through the PI3K pathway.(31, 32) In the presence of 
rapalogs, the feedback loop is abrogated, leading to continued PI3K signaling, TORC2 


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activation, and subsequent phosphorylation of AKT at threonine-308 and serine-473, which 
markedly enhances the activity of AKT.(23, 27, 33, 34) 
In vitro studies have demonstrated that TAK-228 selectively and potently inhibits the mTOR 
kinases with an IC50 of 1.1 nM. Relative to mTOR inhibition, TAK-228 has > 100-fold less 
potency on class I (PI3K isoforms α, β, γ, δ), class II (PI3KC2α and PI3K2Cβ), and class III 
(VPS34) PI3K family members as well as PI4K and PI4Kβ. 
TAK-228, administered orally in multiple human tumor xenograft mouse models, can inhibit 
angiogenesis and tumor growth by inhibiting mTOR signaling at plasma concentrations 
associated with in vitro inhibition of mTOR in a dose- and time-dependent manner. These 
effects display a clear pharmacokinetic (PK)-to-pharmacodynamic relationship.(35) TAK-
228 inhibits both the phosphorylation of S6 and 4E-BP1, the downstream substrates of 
TORC1, and selectively inhibits AKT phosphorylation at serine-473 (S473), as evidenced 
by decreased pAKT, the downstream substrate of TORC2. (31, 35, 36) Dual TORC1/2 
inhibition mitigates the feedback activation of AKT, which is known to facilitate resistance 
to TORC1-only inhibitors such as rapamycin.(37) TAK-228 inhibits mTOR signaling and 
has demonstrated anticancer activity against a number of human solid tumor cell-line 
xenograft mouse models, including phosphatase and tensin homolog (PTEN) mutant 
endometrial, breast, and renal cell carcinomas. 
For detailed information regarding the nonclinical pharmacology and toxicology of TAK-
228 please refer to the Investigator’s Brochure (IB).(38) 
2.2 Nonclinical Experience with TAK117 
Activating somatic missense mutations (eg, E542K, E545K, and H1047R) in the 
phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) gene 
encoding the p110α catalytic subunit of PI3Kα have been identified as a major mechanism 
for PI3K-dependent malignant transformation, proliferation, and survival. PIK3CA 
mutations have been reported to occur in various solid tumors with the highest rates in breast 
(27%), endometrial (24%), bladder (23%), colon (15%), and ovarian (10%) cancers.(39-41) 
In addition to direct mutations of PI3Kα, the pathway may also be activated by mutations or 
overexpression of upstream effectors such as receptor tyrosine kinases (RTKs) including 
human epidermal growth factor receptor 2 (HER2), epidermal growth factor receptor 
(EGFR), and insulin-like growth factor receptor (IGFR). PIK3CA is also amplified in 
several tumor types including the squamous type of NSCLC.(42) 
TAK-117, a selective, small molecule inhibitor of PI3K, has demonstrated greatest 
antiproliferative activity in cell lines harboring PIK3CA activating mutations and/or HER2 
overexpression. TAK-117 inhibited the in vitro biochemical activity of human recombinant 
PI3Kα enzyme with an average IC50 of 21.4 nM and shown similar potency against 
PIK3CA hotspot mutations at E545K and H1047R. TAK-117 was shown to be 50- to 600-
fold less potent against the remaining Class I PI3K isoforms (PI3Kβ, , and ), mTOR. 
2.3 TAK-228 in Combination with TAK-117 (PIKTOR) 
The nonclinical antitumor activity of TAK-228 in combination with TAK-117, known as 
PIKTOR, has been explored in a number of experimental in vitro and in vivo tumor models. 


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To investigate the effect of PIKTOR on the downstream cellular signaling of the 
PI3K/AKT/mTOR pathway, Western blot analysis was performed using a diverse group of 
human tumor cell lines treated with PIKTOR as a single agent or in combination. The 
treatment of PIKTOR resulted in greater inhibition of these targets than either single agent. 
Additionally, treatment with PIKTOR induced greater apoptosis, as indicated by decreased 
levels of total PARP (poly ADP ribose polymerase). Further, the antiproliferative effect of 
PIKTOR was determined against a diverse group of human tumor cell lines in vitro and in 
vivo. The combination exhibited at least additive activity in all other cell lines tested 
(HCC1419, HCC1954, MDA-MB-468, MDA-MB-436 [breast tumor], A549, NCI-H460, 
and NCI-H596 [lung carcinoma]). The level of inhibition observed was greater for PIKTOR 
than either single agent alone. Antitumor activity of PIKTOR was assessed in 3 xenograft 
models in mice: 2 breast cancer cell line models, HCC70 (triple negative breast cancer, 
PTEN null) and MDA-MB-361 (HER2 amplified breast cancer with mutated PIK3CA), and 
1 colorectal cancer model, HCT-116 (KRAS and PIK3CA mutations). The treatment of 
PIKTOR was tolerated and resulted in a statistically significant (p < 0.001) increase in 
antitumor effects when compared with single-agent treatment in multiple treatment 
schedules in these xenograft models. 
The principal adverse effects associated with the administration of each agent are consistent 
with their respective mechanisms of action. Based on the available single-agent nonclinical 
and clinical safety data for PIKTOR, the expected overlapping nonclinical combination 
toxicities (including bone marrow and lymphoid depletion, effects on glucose/insulin 
homeostasis including hyperglycemia, and potential effects on chloride and cholesterol 
levels) can be monitored with routine clinical hematology and serum chemistry evaluations, 
and are expected to be reversible and manageable in the clinic. Results from in vitro drug 
metabolism and pharmacokinetic studies suggest that the potential for DDIs between 
PIKTOR in humans is low. 
For detailed information regarding the nonclinical pharmacology of PIKTOR please refer to 
the PIKTOR IB.(43) 
3.    
SUMMARY OF CLINICAL EXPERIENCE 
3.1 Clinical Experience with TAK-228 
TAK-228 is in clinical development as a single agent in 3 phase 1 studies including study 
INK128-01 in patients with advanced solid malignancies (44), study INK128-002 in patients 
with multiple myeloma, non-Hodgkin lymphoma and Waldenström macroglobulinemia (45) 
and study C31002 to measure the effect of TAK-228 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 receptor-positive /human epidermal growth factor receptor 2 protein-negative) 
advanced or metastatic breast cancer (Ph1b/2 study C31001). 
TAK-228 dosing regimens tested in these studies included 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). 


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A new TAK-228 capsule containing milled active pharmaceutical ingredient (API) was 
developed to allow scaled-up production. The milled API, could result in a faster absorption 
profile with possibly higher maximum concentration (Cmax), which could present a 
different safety profile compared to the previous unmilled API capsules. Therefore, an 
additional study: A Phase I, open label study to evaluate the safety, tolerability, and 
pharmacokinetics of TAK-228 as a single agent and in combination with paclitaxel in adult 
patients with advanced non-hematological malignancies (study TAK-228-1004), was 
designed to determine the recommended phase 2 dose (RP2D) for single agent milled TAK-
228 (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. 
The following table (Table 1) summarizes TAK-228 doses, schedules, active pharmaceutical 
ingredient (API) and PK population investigated in all studies. Details on PK and safety 
information for each study are available in the current IB edition.(38) 
 
Table 1. 
Summary of TAK-228 Clinical Studies 
 


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3.2 Clinical Experience with TAK-117 
TAK-117 is currently being investigated both as a single agent and in combination with 
chemotherapy or other targeted therapies for the treatment of advanced solid tumors. As of 
the clinical data cutoff date (22 June 2015), the safety, tolerability, and PK data of single-
agent TAK-117 evaluated in 1 FIH, dose-finding study in patients with advanced 
nonhematologic malignancies (Study INK1117-001) is available in the IB. Three additional 
clinical studies (MLN1117-1002, MLN1117-1003 and MLN1117-1501) are ongoing. A 
tabular summary of the studies is presented below (Table 2). 
TAK-117 is also being investigated in combination with TAK-228 in study C32001 as 
described in Table 3. 
 
 
. 
 


 
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Table 2. 
Summary of TAK-117 Clinical Studies  
 
Study No.
Study Design/Population 
Dosing Regimen / 
Dose (Number of patients) 
Status
   
 
INK1117-001 
 
Phase 1
                    Open-label, multicenter, dose-escalation / 
Adult patients (aged ≥18 years) with advanced solid 
tumors 
Process A capsules: 
•   QD: 100, 150, 200, 300 mg (n=24) 
•   MWF QW: 200, 300, 400, 600, 900, 1200 mg (n=27) 
•   MTW QW: 200, 400, 600, 900 mg (n=20) 
Process B capsules: 
•   MWF QW: 600, 900, 1200 mg (n=13) 
•   MTW QW: 600, 900, 1200, 1500 mg (n=15) 
•   BID on MWF QW: 300, 400, 500, 600 mg (n=22)  
 
Enrolling
MLN1117-1003                  
Phase 1b
Open-label, multicenter, 4-arm combination, dose-
escalation/ 
Adult patients (aged ≥18 years) with advanced or 
metastatic gastric or gastroesophageal adenocarcinoma 
• 
Part 1: lead-in dose escalation in patients with 
advanced solid tumors, including gastric cancer 
• 
Part 2: expansion at MTD or RP2D 
 
 
Cohorts A-C (28-day cycles):   
 
 
            Enrolling 
o 
TAK-659 (PO QD each week) 
+MLN1117 (MTW QW) 
o 
Alisertib (40 mg PO BID MTW, Wks 1-3) 
+MLN1117 (MTW QW) 
o 
Paclitaxel (80 mg/m2 IV M QW, Wks 1-3) 
+MLN1117 (TWTh QW) 
Cohort D (21-day cycles): 
o 
MLN1117 (MTW QW) 
+docetaxel (75 mg/m2 IV M, Wk 1 only) 
 
MLN1117-1501 
Phase 1b/2 
                  Adaptive, open-label 2-arm dose-escalation / 
Adult patients (aged ≥18 years) with advanced or 
metastatic NSCLC 
21-day cycles: 
● 
Escalation: MLN1117 (TWTh QW) 
+docetaxel (36 mg/m2 IV M, Wks 1-2) 
● 
Expansion (2 treatment arms): 
Enrolling 
● 
Part 1: dose escalation 
 
● 
Part 2: sequential, multistage, adaptive, 
randomized phase 2 expansion at MTD or RP2D 
o 
MLN1117 (TWTh Wks 1-3) 
+docetaxel (36 mg/m2 IV M, Wks 1-2) 
o 
Docetaxel single agent (75 mg/m2 IV M, Wk 1 
 only) 
 
C32001 
Phase 1b 
Multicenter, open-label, safety, and PK. 
Adult patient (aged ≥ 18 years) with advanced 
nonhematologic malignancies 
 
• 
Dose escalation (3+3) 
• 
Expansion (mutual PK DDI; tumor-specific 
cohorts) 
 
28-day cycles: 
o 
Escalation: (includes milled TAK-228) 
o 
Arm A: TAK-228 QD+TAK-117 
QD x3d (MWF) QW 
o 
Arms B & C: TAK-228+TAK-117 
QDx3d (MTW) QW 
o 
Expansion: (2 arms) 
o 
TBD per escalation 
Enrolling 
 
Abbreviations: BID=twice daily, EU=European Union, IV=intravenous, M=Monday, MTD=maximum tolerated dose, MTW=Monday, Tuesday and Wednesday, MWF=Monday, 
Wednesday and Friday, NSCLC=non-small cell lung cancer, PO=orally, QD=once daily, QD=once daily, QW=each week, RP2D=recommended phase 2 dose, TWTh=Tuesday, 
Wednesday and Thursday, UK=United Kingdom, US United States, Wk(s)=week(s). 


 
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3.3 Clinical Experience with TAK-228 + TAK-117 (PIKTOR; study C32001) 
As of the clinical safety data cutoff date (10 March 2015), PIKTOR was being investigated 
in 1 phase 1b study (Study C32001). This study is a multicenter, open-label, phase 1b trial of 
PIKTOR administered to adult patients with advanced nonhematologic malignancies for 
whom standard, curative, or life-prolonging anticancer treatment does not exist or is no 
longer effective.  
PIKTOR is being administered in 28-day dosing cycles, in weekly regimens of TAK-228 
QD+TAK-117 QDx3d (MWF) (Arm A) and TAK-228+TAK117 QDx3d (MTuW) (Arms B 
and C). 
As of the data cutoff, a total of 44 patients had received at least 1 dose of TAK-228 or TAK-
117 in Study C32001 and are included in the Safety Population. 
3.3.1    Pharmacokinetics 
Preliminary PK data from study C32001 suggest that TAK-228 exposures increase with 
dose in the 2 to 8 mg dose range and appear variable across the various cohorts (%CV range 
across all cohorts: 16-90%). TAK-228 in combination with TAK-117 did not accumulate to 
any meaningful extent in plasma and PK appeared broadly consistent with single agent 
TAK-228 PK and TAK-117 in studies INK128-001 and INK1117-001 respectively. 
Although a formal drug interaction evaluation between TAK-228 and TAK-117 has not 
been performed yet in study C32001, these initial findings suggest a lack of a readily 
apparent effect of these agents on each other’s PK when combined. 
Please refer to the TAK-228 IB and TAK-117 IBs for detailed information on the clinical 
PK of the individual molecules.(38, 46) 
3.3.2    Pharmacodynamics 
To date, skin samples collected from a total of 34 patients in Study C32001 have been 
analyzed. Expression of all markers (pS6, p4EBP1, and pNDRG1) in skin was suppressed 
>50% compared to the predose level in a majority of patients in all treatment arms with 
>80% suppression of markers in a subset of patients when measured approximately 2 hours 
postdose on Cycle 1 Day 24. Based upon the time course of PD data available there 
appeared to be a more sustained PD effect (up to 8 hours post-dose) at TAK-117 doses of 
200 mg or greater in combination with TAK-228 when both given in a MTuW schedule. 
3.3.3    Safety 
TAK-228 and TAK-117 are being investigated as single agents in clinical trials for the 
treatment of advanced malignancies. To date, the principal TEAEs associated with the 
administration of each single agent are consistent with their respective MOAs. Clinical 
safety information for TAK-228 and TAK-117 administered as single agents is summarized 
in their respective single-agent IBs.(38, 46) 


 
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As of the clinical data cutoff for the most recent IB (10 March 2015), the 2 agents had been 
co-administered in a single open-label, phase 1b study (Study C32001) in patients with 
advanced nonhematologic malignancies. A total of 44 patients had been treated; 11 were 
ongoing. One on-study death was reported in a patient with a fatal event of dyspnea, which 
was considered by the investigator as not related to study drug. A total of 12 treatment-
emergent SAEs were reported for 9 patients (20%); all SAEs were classified as unrelated 
with the exception of 1 related SAE of Grade 3 enterocolitis. Five patients had discontinued 
due to TEAE (3 with related AEs). The most frequently reported TEAEs, regardless of 
causality, were nausea, fatigue, diarrhea, vomiting, decreased appetite, aspartate 
aminotransferase increased, stomatitis, ALT, constipation, and rash maculo-papular. 
3.3.4    Potential Risks  
The most common TEAEs observed with TAK-228 are consistent with the 
pharmacodynamic mechanism of mTOR inhibition that is also seen with rapalogs (TORC1 
inhibition) or other dual mTORC1/2 inhibitors. The TEAEs observed across the TAK-228 
single-agent studies include diarrhea, fatigue, vomiting, rash, mucosal inflammation, 
asthenia, dysgeusia, thrombocytopenia, stomatitis, blood creatinine increased, 
hyperglycemia, nausea, anorexia, and decreased appetite. 
The identified and potential risks of TAK-228 and TAK-117, including data from 
nonclinical and clinical studies for each product, as well as more detailed information on the 
identified and potential risks of both drugs is included in the individual single-agent IBs and 
in the PIKTOR IB. 
Potential overlapping toxicities associated with TAK-228 and TAK-117 include: 
• Dermatologic disorders (pruritus, rash) 
• Gastrointestinal disorders (diarrhea, mucosal inflammation, nausea, stomatitis, 
vomiting) 
• Generalized disorders (anorexia, asthenia, decreased appetite, fatigue) 
• Hematologic disorders (lymphoid, bone marrow depletion) 
• Metabolic disorders (decreased blood chloride, hypercholesterolemia, 
hyperglycemia) 
On the basis of current clinical experience and the previous list of potential overlapping 
toxicities, hyperglycemia, diarrhea, nausea, vomiting, fatigue, and rash are the most 
anticipated TEAEs associated with the TAK-228 + TAK-117 combination regimen. These 
events are expected to be manageable. 
During this study, risk mitigation strategies include, but are not limited to, strict application 
of the study inclusion and exclusion criteria, frequent monitoring of clinical and laboratory 
results, guidelines for management and prophylaxis of potential toxicities, criteria for dose 
modification, and regular monitoring of TEAEs and serious adverse events (SAEs) by the 
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4.    SPECIAL WARNINGS AND PRECAUTIONS 
4.1 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 TAK-228. 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 fasting blood glucose ≥ 150 mg/dL measured by glucometer would initiate closer 
monitoring of serum glucose and possible intervention. Subjects with Grade 1 
hyperglycemia (fasting serum glucose [FSG] > the upper limit of the normal range 
≤ 160 mg/dL) are treated with oral hypoglycemic agents (eg, metformin), and subjects with 
≥ Grade 2 hyperglycemia (FSG > 160 mg/dL) are treated aggressively with oral 
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 TAK-228-
treated subjects who developed hyperglycemia.  Guidelines for monitoring and treating 
hyperglycemia are provided in all clinical protocols administering TAK-228. 
4.2 Cardiac Effects 
Cardiac events (including QT interval corrected for heart rate prolongation and arrhythmias) 
have been infrequently observed in clinical studies of TAK-228. As of 09 December 2015, 
there has been 1 report of ventricular fibrillation and cardiac arrest post dose that had a fatal 
outcome and was assessed as related to TAK-228 (see IB for further details).(38) 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 TAK-228 studies. 
Preliminary results from a dedicated study of the effects of TAK-228 on the QTc interval 
(study C31002) show lack of clinically relevant effects on QTc interval, PR and QRS 
intervals, minimal effects on heart rate, and absence of treatment-emergent ECG 
morphology findings and therefore the treatment with TAK-228 is not associated with 
clinically meaningful effects on the overall electrocardiographic safety profile (for further 
details refer to current IB version). (38) 
For subjects showing any signs of cardiac instability after TAK-228 dosing, additional 
monitoring onsite before clinic discharge should be considered. 
4.3 Renal Function 
Elevations in creatinine (regardless of causality) have been observed in subjects receiving 
TAK-228, 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 pre-renal 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 
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creatinine. Patients 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. Each dose of TAK-228 should be taken orally with 
8 ounces (240 mL) of water. 
Baseline macroscopic urinalysis and routine serum chemistries along with other safety 
laboratory assessments are performed in all TAK-228 studies. Additionally, microscopic 
urinalysis, a 12-hour urine collection, spot urine electrolytes, protein and creatinine, and 
serum chemistry should be collected at any time when the serum creatinine is ≥ Grade 1, 
according to National Cancer Institute Common Terminology Criteria for Adverse Events 
version 4.0, to further evaluate possible etiologies for the renal dysfunction. 
4.4 Rash 
Rash observed in clinical studies of TAK-228 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. 
4.5 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 TAK-228 administration. 
Symptoms of pneumonitis will be closely monitored in all TAK-228 study subjects. 
4.6 Interactions with other Medicines and other Forms of Interactions 
Clinical drug-drug interaction studies have not been conducted with TAK-228. At this time, 
there are no known drug interactions. In vitro data, including cytochrome P450 
induction/inhibition and transporter inhibition studies conducted for TAK-228, suggest a 
low risk for TAK-228 to precipitate a drug-drug interaction. Although potential drug-drug 
interactions with TAK-228 cannot be ruled out based on the known metabolism 
characteristics of TAK-228, the potential risk is considered low. 
5. RATIONALE FOR THE RP2D FOR PIKTOR (TAK-228 + TAK-117) 
Study C32001 is an ongoing open-label study designed to determine the MTD and DLTs for 
oral administration of milled TAK-228 given in combination with TAK-117 and was 
designed to characterize the safety and tolerability of escalating doses of TAK-228 and/or 
TAK-117 in patients with advanced solid tumors. The study features a dose-escalation phase 
evaluating 3 dosing schedules. A favorable tolerability profile was observed when 
increasing doses of TAK-228 (3–8 mg) were administered with a fixed dose of TAK-117 
(both given QD × 3d QW). The MTD for TAK-228 in combination with TAK-117 both 
given QD × 3d QW was 6 mg TAK-228 + 200 mg TAK-117. 
 
 
 


 
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Table 3. 
Study C32001 Treatment Schema PIKTOR Dose Limiting Toxicity 
 
 
While both combination dose levels were considered safe based on 3+3 rules, the lower dose 
level of 4 mg + 200 mg QD × 3d QW was chosen as the RP2D for milled TAK228 + TAK-
117 for further development. 
6. STUDY RATIONALE 
The hypothesis of this pilot trial is that administration of the oral combination of TAK-228 
and TAK-117 will inhibit NHEJ in metastatic TNBC leading at the time of disease 
progression to metastases that are HR-deficient and sensitive to cisplatin plus nab paclitaxel 
therapy. The exceptional responder patient’s treatment history described in the Introduction 
provides the clinical rationale for the present trial which will utilize PIKTOR to inhibit HR 
proficiency prior to administration of cisplatin plus nab paclitaxel. The trial will include in 
depth analysis of the patients’ TNBC genome and phosphoproteome to evaluate HR-
proficiency and deficiency, and nuclear proteins that drive NHEJ, before and upon 
progression with PIKTOR therapy.  
 
7. STUDY OBJECTIVES 
7.1    Primary Objectives 
The primary objective of this study is to assess the objective response rate associated with 
sequential treatment with the oral combination of TAK-228 and TAK-117 (PIKTOR) 
followed, upon progression on PIKTOR, by cisplatin plus nab-paclitaxel in metastatic triple 
negative breast cancer (metTNBC) patients. 
7.2    Secondary Objectives 
To assess the safety and duration of response to sequential treatment with the oral 
combination of TAK-228 and TAK-117 (PIKTOR) followed by cisplatin plus nab-paclitaxel 
in metastatic TNBC patients. 
To assess the metastatic TNBC tissues for homologous recombination proficiency and 
deficiency by evaluating inactivating mutations in HR genes on Next Generation 
Sequencing (NGS), the overall and pattern-specific mutational load in the cancers on NGS, 
as well as collect frozen and/or formalin-fixed paraffin embedded (FFPE) tissue for 
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8.    
STUDY ENDPOINTS 
8.1    Primary Endpoints  
The primary endpoints of this study are to assess the objective response rate associated with 
sequential treatment with the oral combination PIKTOR followed by nab-paclitaxel plus 
cisplatin in metastatic TNBC. 
8.2    Secondary Endpoints 
The secondary endpoints of this study are safety and duration of response associated with 
sequential treatment with the oral combination PIKTOR followed by nab-paclitaxel plus 
cisplatin, as well as homologous recombination deficiency, next-generation sequencing, and 
collection of frozen and/or formalin-fixed paraffin embedded (FFPE) tissue for biomarker 
development. 
9.    
STUDY DESIGN  
9.1    Overview of Study Design 
This exploratory open label pilot trial will evaluate the sequential administration of PIKTOR 
followed by nab-paclitaxel plus cisplatin in patients with metastatic TNBC. 
Patients will receive 4 mg PO TAK-228 and 200 mg PO TAK-117, administered together 
QDx3d QW, continuously (eg, Monday-Tuesday-Wednesday each week) until disease 
progression.  
Patients will then receive treatment with standard nab paclitaxel 175 – 220 mg/m2 plus 
cisplatin 60 – 75 mg/m2 with standard pegylated filgrastim 6 mg SC administered every 
3 weeks until disease progression or for a maximum of 6 cycles. Dosing of chemotherapy 
will be determined per cycle, per physician’s discretion. NOTE: Patients have the option to 
switch to carboplatin (AUC of 5 – 6) given every 3 weeks instead of cisplatin due to 
cisplatin toxicity, and remain on study. The dose and choice of cisplatin or carboplatin will 
be determined per cycle, per physician’s discretion, based on patient’s cumulative toxicity 
from cisplatin. 
Patients will undergo core needle biopsies of metastatic locoregional or pulmonary or 
hepatic disease prior to the start of PIKTOR treatment, and at the time of disease 
progression on PIKTOR (prior to beginning nab paclitaxel plus cisplatin) for NGS and 
biomarker development. If a research biopsy from a patient’s metastatic disease cannot be 
safely obtained, a skin biopsy is permitted. 
Patients who have residual locally recurrent or metastatic disease upon completion of nab 
paclitaxel/cisplatin may be treated with standard of care breast cancer therapies off study, at 
the recommendation of the treating physician. 


 
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9.2    Number of Patients 
Twenty patients with metastatic TNBC will be enrolled over 12-18 months. The enrollment 
process begins when the Coordinator has obtained a signed informed consent form. See 
Section 11.5.2 for registration procedures. 
9.3    Duration of Study 
The duration of patient participation in the study will be a maximum of 18 months. 
 
10.    STUDY POPULATION 
10.1    
Inclusion Criteria 
Each patient must meet all of the following inclusion criteria to be enrolled in the study: 
1. Female patients 18 years or older.  
2. Have a diagnosis of metastatic TNBC, including de novo metastatic TNBC.(18) 
3. Have not received more than 3 prior chemotherapy regimens for metastatic disease. 
Prior platinum and/or taxane therapy in the adjuvant or metastatic setting is 
permitted. 
4. Androgen receptor-negative (less than 10% positive nuclei) on standard IHC 
performed at the local pathology laboratory. 
5. Have locoregional (eg, breast, chest wall, regional lymphatic) or pulmonary or 
hepatic metastatic disease that is amenable to core needle biopsy. If a research 
biopsy from a patient’s metastatic disease cannot be safely obtained, a skin biopsy is 
permitted. 
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 (See 
Appendix I) 
7. Female patients who: 
a. Are postmenopausal for at least 1 year before the screening visit, OR 
b. Are surgically sterile, OR 
c. If they are of childbearing potential, agree to practice 1 effective methods of 
contraception and 1 additional effective (barrier) method, at the same time, from 
the time of signing the informed consent through 90 days (or longer as mandated 
by local labeling [eg, USPI, SmPC, etc,]) after the last dose of study drug, OR 
d. Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the patient. (Periodic abstinence [eg, calendar, ovulation, 
symptothermal, postovulation methods], withdrawal, spermicides only, and 
lactational amenorrhea are not acceptable methods of contraception. Female and 
male condoms should not be used together.) 
8. Screening clinical laboratory values as specified below: 


 
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a. Bone marrow reserve consistent with: absolute neutrophil count (ANC) ≥ 1.5 x 
109/L; platelet count ≥ 100 x 109/L; hemoglobin ≥ 9 g/dL without transfusion 
within 1 week preceding study drug administration 
b. Hepatic: total bilirubin ≤ 1.5 x upper limit of normal (ULN), transaminases 
(aspartate aminotransferase/serum glutamic oxaloacetic transaminase-
AST/SGOT and alanine aminotransferase/serum glutamic pyruvic transaminase-
ALT/SGPT) ≤ 2.5 x ULN (≤ 5 x ULN if liver metastases are present); 
c. Renal: creatinine clearance ≥60 mL/min based either on Cockroft-Gault estimate 
(See Appendix II) or based on urine collection (12 or 24 hour); 
d. Metabolic: Glycosylated hemoglobin (HbA1c)<7.0%, fasting serum glucose 
(≤ 130 mg/dL) and fasting triglycerides ≤ 300 mg/dL 
9. Ability to swallow oral medications. 
10. Must be able to fast for glucose monitoring throughout PIKTOR treatment. 
11. Patients who have a history of brain metastasis are eligible for the study provided 
that all the following criteria are met: 
a. Brain metastases which have been treated 
b. No evidence of disease progression for ≥2 months before the first dose of study 
drug. 
c. No hemorrhage after treatment 
d. Off-treatment with dexamethasone for 3 weeks before administration of the first 
dose of PIKTOR 
e. No ongoing requirement for dexamethasone or anti-epileptic drugs 
12. Voluntary written consent must be given before performance of any study related 
procedure not part of standard medical care, with the understanding that consent may 
be withdrawn by the patient at any time without prejudice to future medical care. 
10.2    
Exclusion Criteria 
Patients meeting any of the following exclusion criteria are not to be enrolled in the study: 
1. Leptomeningeal disease that is symptomatic or cytology-proven. 
2. Other clinically significant co-morbidities, such as uncontrolled pulmonary disease, 
active central nervous system disease, active infection, or any other condition that 
could compromise the patient’s participation in the study. 
3. Known human immunodeficiency virus infection. 
4. Known hepatitis B surface antigen-positive, or known or suspected active hepatitis C 
infection. 
5. Any serious medical or psychiatric illness that could, in the investigator’s opinion, 
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6. 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 non-melanoma skin cancer or 
carcinoma in situ of any type are not excluded if they have undergone complete 
resection. 
7. Breast feeding or pregnant. 
8. Treatment with any investigational products within 30 days before the first dose of 
study drug 
9. Previous treatment with PI3K, AKT, dual PI3K/mTOR inhibitors, TORC1/2 
inhibitors or TORC1 inhibitors. 
10. Manifestations of malabsorption due to prior gastrointestinal (GI) surgery, GI 
disease, or for an unknown reason that may alter the absorption of PIKTOR. In 
addition, patients with enteric stomata are also excluded. 
11. History of any of the following within the last 6 months before administration of the 
first dose of the drug: 
a. Ischemic myocardial event, including angina requiring therapy and artery 
revascularization procedures   
b. Ischemic cerebrovascular event, including transient ischemic attack and artery 
revascularization procedures 
c. Requirement for inotropic support (excluding digoxin) or serious (uncontrolled) 
cardiac arrhythmia (including atrial flutter/fibrillation, ventricular fibrillation or 
ventricular tachycardia)  
d. Placement of a pacemaker for control of rhythm 
e. New York Heart Association (NYHA) Class III or IV heart failure (See 
Appendix III)   
f. Pulmonary embolism  
12. Significant active cardiovascular or pulmonary disease including: 
a. Uncontrolled hypertension (ie, systolic blood pressure >180 mm Hg, diastolic 
blood pressure > 100 mm Hg). Use of anti-hypertensive agents to control 
hypertension before Cycle1 Day 1 is allowed. 
b. Pulmonary hypertension   
c. Need for supplemental oxygen 
d. Significant valvular disease; severe regurgitation or stenosis by imaging 
independent of symptom control with medical intervention, or history of valve 
replacement   
e. Medically significant (symptomatic) bradycardia    
f. History of arrhythmia requiring an implantable cardiac defibrillator   


 
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g. Baseline prolongation of the rate-corrected QT interval (QTc) (eg, repeated 
demonstration of QTc interval > 480 milliseconds, or history of congenital long 
QT syndrome, or torsades de pointes)  
13. Poorly controlled diabetes mellitus defined as glycosylated hemoglobin (HbA1c) > 
7%; patients with a history of transient glucose intolerance due to corticosteroid 
administration may be enrolled in this study if all other inclusion/exclusion criteria 
are met.  
14. Treatment with strong inhibitors and/or inducers of cytochrome P450 (CYP) 3A4, 
CYP2C19 or CYP2C19 within 1 week preceding the first dose of study drug (See 
Appendix IV). 
15. Patients receiving systemic corticosteroids (either IV or oral steroids, excluding 
inhalers or low-dose hormone replacement therapy) within 1 week before 
administration of the first dose of study drug. 
16. Daily or chronic use of a proton pump inhibitor (PPI) and/or having taken a PPI 
within 7 days before receiving the first dose of study drug 
11.    STUDY TREATMENT ADMINISTRATION 
1. Once patients sign informed consent, they will be evaluated with a complete history, 
physical examination as well as initial studies as described in Section 11.5. 
2. Metastatic TNBC Patients will receive 4 mg PO TAK-228 and 200 mg PO TAK-
117, administered together once per day, 3 days per week (QD x 3d QW), 
continuously (eg, Monday-Tuesday-Wednesday each week) until disease 
progression.  
3. Upon disease progression on PIKTOR, patients will be treated with standard nab 
paclitaxel 175 – 220 mg/m2 plus cisplatin 60 – 75 mg/m2 with standard pegylated 
filgrastim 6 mg SC administered every 3 weeks until disease progression or for a 
maximum of 6 cycles. Dosing of chemotherapy will be determined per cycle, per 
physician’s discretion. NOTE: Patients have the option to switch to carboplatin 
(AUC of 5 – 6) given every 3 weeks instead of cisplatin due to cisplatin toxicity, and 
remain on study. The dose and choice of cisplatin or carboplatin will be determined 
per cycle, per physician’s discretion, based on patient’s cumulative toxicity from 
cisplatin. 
4. Patients will undergo core needle biopsies of metastatic locoregional or pulmonary 
or hepatic disease prior to the start of treatment, and upon disease progression on 
PIKTOR (prior to starting nab paclitaxel plus cisplatin) for NGS and biomarker 
development. If a research biopsy from a patient’s metastatic disease cannot be 
safely obtained, a skin biopsy is permitted. 
5. Patients who have residual locally recurrent or metastatic disease upon completion of 
nab paclitaxel/cisplatin may be treated with standard of care breast cancer therapies 
off study, at the recommendation of the treating physician. 
The treatment schema is shown in Table 4. 


 
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Table 4. 
Treatment schema 
Agent 
Dose 
Frequency of 
administration 
Route of 
administration 
TAK-228 
4 mg 
aQD x 3 days, QW 
PO 
TAK-117 
200 mg 
aQD x 3 days, QW 
PO 
Nab-Paclitaxelb 
175 – 220 mg/m2 
Cycle 1-6,  
Day 1, 
q21 days 
IV  
Cisplatinb,c  
60 – 75 mg/m2 
Cycle 1-6,  
Day 1, 
q21 days 
IV 
Pegfilgrastim 
6 mg 
Cycle 1-6,  
Day 1 or Day 2 
SC 
aThe 3 days of treatment with TAK-228 and TAK-117 should be continuous, eg, Monday-Tuesday-
Wednesday each week. 
bNab-paclitaxel plus cisplatin treatment will begin upon disease progression on PIKTOR. Dosing of 
chemotherapy will be determined per cycle, per physician’s discretion.  
cPatients have the option to switch to carboplatin (AUC of 5 – 6) given every 3 weeks instead of 
cisplatin due to cisplatin toxicity, and remain on study. The dose and choice of cisplatin or carboplatin 
will be determined per cycle, per physician’s discretion, based on patient’s cumulative toxicity from 
cisplatin. 
 
11.1    
PIKTOR Administration 
All protocol-specific criteria for administration of TAK-228 + TAK-117 (PIKTOR) must be 
met and documented before drug administration. Study drug will be administered only to 
eligible patients under the supervision of the investigator. 
TAK-228 + TAK-117 will be administered on an empty stomach. It is recommended that 
each dose of TAK-228 + TAK-117 be given PO with 8 ounces (240 mL) of water. Patients 
should be instructed to refrain from eating and drinking (except for water and prescribed 
medications) for 2 hours before and 1 hour after each dose. 
Patients must 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 
(NOTE: on clinic visit days, when fasting serum glucose must be taken 2 hrs after study 
drug administration, it is acceptable for patients to take their doses at a different time than is 
typical).  
TAK-228 and TAK-117 must always be taken together, at the same time, when dosed on the 
same day. Patients must 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 TAK-228 + 
TAK-117 doses within the time frame specified (± 12 hours of the QD × 3days per week 
schedule), then the doses will be skipped and considered missed doses. Patients will record 
any missed doses in their diary and resume drug administration at the next scheduled time 
with the prescribed dosage. Under no circumstance will a patient repeat a dose or double-up 
doses. 
If severe emesis or mucositis prevents the patient from taking scheduled doses, that dose 
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readministered, and patients should resume dosing at the next scheduled time with the 
prescribed dosage. Patients will record the occurrence of the emesis in their dosing diaries. 
Under no circumstance will a patient repeat a dose or double-up doses. 
Study drug will be administered only to eligible patients under the supervision of the 
investigator or identified sub-investigator(s). 
11.2    Chemotherapy Administration 
In this protocol, the following chemotherapy products are FDA-approved for MBC: 
• Nab-paclitaxel and cisplatin 
• Supportive therapy (ie, pegfilgrastim) 
Preparation and administration will be followed per the site’s guidelines and standard FDA 
labeling. The doses to be used for nab-paclitaxel and cisplatin are below, and in Table 4 
(dosing of chemotherapy will be determined per cycle, per physician’s discretion): 
• Nab paclitaxel: 175 – 220 mg/m2 administered IV every 3 weeks (Day 1 every 
21 days)  
• Cisplatin: 60 – 75 mg/m2 administered IV every 3 weeks (Day 1 every 21 days) 
• Pegfilgrastim: 6 mg SC, Cycles 1-6, Day 1 or Day 2 
NOTE: Patients have the option to switch to carboplatin (AUC of 5 – 6) given every 
3 weeks instead of cisplatin due to cisplatin toxicity, and remain on study. The dose and 
choice of cisplatin or carboplatin will be determined per cycle, per physician’s discretion, 
based on patient’s cumulative toxicity from cisplatin. 
11.3    TAK-228 Dose-Modification Guidelines  
The primary principle for dose reduction in TAK-228 + TAK-117 is to maintain the 200-
mg dose of TAK-117, which is considered a minimally efficacious dose in the combination 
of TAK-228 + TAK-117. Thus, the dose of TAK-228 will be reduced if necessary while the 
dose and schedule of TAK-117 is maintained when study drug administration is resumed, in 
the event of a needed dosing interruption for toxicity (see Table 5 below). 
If the Grade 3 or greater event that led to dose interruption resolves to Grade 1 or baseline 
value within 3 weeks of interrupting treatment, then the patient may resume combination 
study treatment if treatment with study drug is thought to be beneficial for the patient by the 
investigator. In this case, the patient may resume study treatment with TAK-117 at 200 mg 
QD x 3 days and TAK-228 reduced by 1 dose level. 
TAK-228 and TAK-117 should be administered in continuous cycles, which should 
continue unless the patient has a Grade 3 or greater TAK-228- and/or TAK-117-related 
event. Please refer to the guidelines for dose interruption and for dose reduction in Section 
11.3.1. 
11.3.1      Criteria for Dose Interruption during a PIKTOR Cycle 
Administration of TAK-228 + TAK-117 should be withheld for treatment-related toxicities 
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following nonhematologic toxicities attributed to TAK-228 and/or TAK-117 would not 
require dose interruption: 
• Grade 3 or higher nausea and/or emesis in the absence of optimal anti-emetic 
prophylaxis (Optimal anti-emetic prophylaxis is defined as an anti-emetic regimen 
that employs both a 5-HT3 antagonist and a corticosteroid given in standard doses 
and according to standard schedules). 
• Grade 3 or higher diarrhea that occurs in the absence of optimal supportive therapy 
• Grade 3 fatigue 
Table 5. 
Dose Reduction Schedule for TAK-228 and TAK-117 
Dose Level 
TAK-228 Dose 
TAK-117 Dose 
TAK-228 Capsules and Strength 
  0 
4 mg QD x 3d 
QW 
200 mg QD x 3d 
QW 
One 3 mg capsule and 1-mg capsule 
-1 
3 mg QD x 3d 
QW 
200 mg QD x 3d 
QW 
One 3 mg capsule 
-2 
2 mg QD x 3d 
QW 
200 mg QD x 3d 
QW 
Two 1 mg capsules 
-3 
1 mg QD x 3d 
QW 
200 mg QD x 3d 
QW 
One 1 mg capsule 
 
11.3.2 
Criteria for Discontinuation of PIKTOR 
In general, TAK-228 + TAK-117 dosing should be withheld for ≥ Grade 3 TAK-228 and/or 
TAK-117-related non-hematologic toxicities.  If TAK-228 + TAK-117 dosing is delayed 
because of TAK-228 and/or TAK-117-related toxicities for > 21 consecutive days despite 
supportive treatment per standard clinical practice or if >3 TAK-228 dose reductions are 
required, TAK-228 + TAK-117 therapy will be stopped and the patient will be discontinued 
from the study, and the EOT visit will be completed within 30 to 40 days of the last 
administration of TAK-228 + TAK-117. 
11.3.3  Dose Modifications for Chemotherapy Treatment Associated Toxicity 
Standard of care dose modifications are to be made according to the system showing the 
greatest degree of toxicity and per physician’s discretion. Toxicities will be graded 
according to the NCI CTCAE Version 4.03 as linked in Appendix V. Each chemotherapy 
treatment cycle will begin only when:  
• ANC ≥1000 
• Platelets ≥100,000 
• Resolution of non-hematologic toxicities to ≤Grade 1 or baseline 
For hematologic toxicity, treatment decisions on standard of care drug should be made 
based on ANC and platelet counts on the day of treatment administration. Dose 
modifications must be recorded on the CRF. 
• Patients must have ANC of ≥1000/mm3 on Day 1 of each cycle (if pegfilgrastim is 
being used) or of ≥1200/mm3 on Day 1 (if no pegfilgrastim is being used) to 


 
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receive scheduled treatment. Treatment may be delayed to allow sufficient time 
for recovery. 
• Patients must have a platelet count of ≥100,000/mm2 on Day 1 of each cycle to 
receive scheduled chemotherapy treatment. Nab-paclitaxel and cisplatin should 
be delayed until platelet counts recover to ≥100,000/mm2 and then treated with 
either full dose or reduced dose chemotherapy at the physician’s discretion. 
Treatment may be delayed to allow sufficient time for recovery. 
NOTE: Patients have the option to switch to carboplatin (AUC of 5 – 6) given every 
3 weeks instead of cisplatin due to cisplatin toxicity, and remain on study. The dose and 
choice of cisplatin or carboplatin will be determined per cycle, per physician’s discretion, 
based on patient’s cumulative toxicity from cisplatin. 
Use of hematopoietic growth factors to ameliorate hematologic toxicity is at the discretion 
of the physician investigator and should be in accordance with the American Society of 
Clinical Oncologists (ASCO) guidelines. 
11.4  Chemotherapy Treatment Delay or Discontinuation 
If a treatment day variation is needed for reasons other than toxicity, an attempt should be 
made to keep the variation within the following parameters: 4 calendar days. Any delay 
within this window is NOT a deviation. Note: This delay window does not apply to Cycle 1.  
1. Treatment may be delayed no more than 3 weeks for any reason (Note: Delays do not 
count scheduled weeks of rest). 
2. Patients who are off study treatment for more than 3 weeks for any reason will be 
considered off treatment.  
11.5    
Schedule of Assessments 
The schedule of assessments for the trial is shown in Appendix VI. If a required observation 
or procedure is missed, documentation is required in the source records, on the Protocol 
Deviation Form, and on the CRF, to explain the reason for this protocol deviation. 
11.5.1  Prestudy Assessments 
Note: Assessments that are part of the standard of care and obtained within 3- 4 weeks of 
prestudy assessment visit, are acceptable as part of the screening tests. Results of such 
tests will be acceptable even if obtained prior to the execution of the Inform Consent.  
Prior to entry into the study, the following assessments will be performed to determine if 
patient is eligible to continue in the study as per Sections 10.1 and 10.2 describing the 
inclusion and exclusion criteria for the study. 
1. A signed Patient Informed Consent Form must be obtained. 
2. A signed Patient Authorization Form (HIPAA) must be obtained. 
3. It has been confirmed that the patient meets all inclusion criteria and none of the 
exclusion criteria. 
4. A complete medical history must be obtained within 3 weeks prior to registration. 


 
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5. A complete physical examination (including vital signs, height, and body weight) must 
be obtained within 3 weeks prior to registration. 
6. Assessment of PS on the ECOG scale (Appendix I) must be obtained within 3 weeks 
prior to registration. 
7. Assessment of concomitant medications must be obtained within 4 weeks prior to 
registration. 
8. A complete blood count (CBC) with differential and platelet count within 4 weeks 
prior to registration. 
9. Complete metabolic profile (CMP) including: serum chemistries (creatinine, glucose, 
total protein, blood urea nitrogen [BUN], total carbon dioxide [CO2], albumin, total 
bilirubin, alkaline phosphatase, and aspartate transaminase [AST] and alanine 
transaminase [ALT]) and electrolytes (total calcium, chloride, potassium, sodium), must 
be performed within 4 weeks prior to registration.  
10. Coagulation (PT/INR, aPTT) must be performed within 3 weeks prior to registration. 
11. Fasting lipid profile must be performed within 3 weeks prior to registration. 
12. HbA1c must be performed within 3 weeks prior to registration. 
13. Fasting serum glucose must be performed within 3 weeks prior to registration. 
14. Females of childbearing potential must have a serum or urine pregnancy test performed 
within 7 calendar days prior to registration. 
15. Urinalysis must be performed within 4 weeks prior to registration. 
16. EKG must be performed within 4 weeks prior to registration. 
17. Pulmonary function tests, only if clinically indicated, must be performed within 
4 weeks prior to registration. 
18. A clinical assessment of the patient’s disease (ie, by physical examination) must be 
performed within 3 weeks prior to registration.  
19. Radiological assessment of tumors (ie, chest and abdomen CT scan, radionuclide bone 
scan) must be performed within 4-6 weeks of registration. The methods used for 
prestudy assessments should be used throughout the study. If possible, the same 
equipment should be used each time. 
20. Assessments of other lesions must be performed within 4 weeks prior to registration. 
21. If safely accessible, research biopsies of the patient’s metastatic locoregional or 
pulmonary or hepatic disease must be obtained prior to the first day of treatment. If a 
research biopsy from a patient’s metastatic disease cannot be safely obtained, a skin 
biopsy is permitted. 
22. Whole blood collection (40 mL) for germline exome sequencing studies. 
23. Distribution of patient diaries: 1) PIKTOR dosing, and 2) in-home glucometer readings 
(see Appendices). 
11.5.2  Registration Procedures 
Written documentation of full, noncontingent IRB approval must be on file before a patient 
can be registered. The registration process begins when the Coordinator has obtained a 
signed informed consent.  
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and date of patient discontinuation are to be recorded on the Patient/Enrollment Log by the 
Coordinator. The Patient/Enrollment Log will be maintained for review for any reason (ie, 
monitoring/audit). Once a study ID is assigned, this will constitute the registration 
confirmation. Treatment must begin within 10 working days (not counting the day of 
dosing) after the patient’s registration on the study.  
The PI may be allowed the opportunity to review and grant exceptions for minor deviations 
in eligibility, in order to maximize patient accrual without jeopardizing patient safety or 
scientific integrity of these studies. Examples might include minor deviations of baseline 
labs, timing of prior treatment or tests, etc. It is recognized that these questions arise 
frequently. The procedure to be followed is for the Investigator or his/her representative (ie, 
research nurse) to e-mail the request to the PI for an exception. The PI would then make a 
determination, which is binding. In no instance should this exception constitute a safety 
issue for the patient or a significant deviation from the scientific purpose of the study. 
11.5.3  Assessments During Treatment 
11.5.3.1 
Assessments During PIKTOR 
The following assessments will be performed during therapy prior to the start of each cycle, 
unless otherwise specified. A PIKTOR Cycle is defined as 28 days. Patients will continue 
PIKTOR until disease progression. 
There is a window (up to 4 calendar days prior to the scheduled time point) for 
assessments during the study. Any delay within this window is NOT a deviation. 
Assessments that are to be done on days when study drug is administered must be done 
prior to dosing as these assessments (CBC, CMP, assessment of response, etc) may 
determine whether or not drug is administered, or if a dose reduction is necessary, unless 
otherwise noted.  
1. A brief medical history, to capture events that have occurred since the last cycle. Events 
that were not captured in the baseline complete medical history should be recorded on 
the AE page of the CRF. 
2. A brief physical examination, including vital signs and body weight. 
3. ECOG performance status (PS) 
4. Assessment of concomitant medications 
5. A CBC with differential and platelet count every 14 days for the first Cycle, Day 1 of 
cycles thereafter. 
6. A CMP every 14 days for the first Cycle, Day 1 of cycles thereafter. 
7. Coagulation (PT/INR, aPTT) 
8. Fasting lipid profile 
9. HbA1c must be obtained Cycle 1 Day 1, Cycle 3 Day 1 and every 3 cycles thereafter.  
10. Fasting serum glucose (in-clinic): patients are required to fast overnight (nothing except 
water and/or medications after midnight or for a minimum of 8 hrs). The blood sample 
should be taken approximately 2 hrs after study drug administration with the patient 
continuing to fast until the blood sample is taken. See Section 11.9.1. NOTE: on clinic 
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administration, it is acceptable for patients to take their doses at a different time than is 
typical.  
11. Fasting serum glucose (in-home): patients will be given a glucometer to monitor their 
daily fasting blood glucose performed daily from Cycle 1 Day 2 through last dose of 
PIKTOR, and may be decreased to once weekly after the first 2 months, per Section 
11.9.1.  
12. Urinalysis must be obtained prior to Day 1 and Day 15 for Cycle 1, and on Day 1 every 
subsequent cycle.  
13. Serum or urine pregnancy test 
14. EKG, as clinically indicated. 
15. Tumor response by clinical assessment of the patient’s disease (ie, by physical 
examination)  
16. Radiological assessment of tumors (ie, chest and abdomen CT scan, radionuclide bone 
scan) as clinically indicated. The methods used for prestudy assessments should be used 
throughout the study. If possible, the same equipment should be used each time.  
17. If safely accessible, research biopsies of the patient’s metastatic locoregional or 
pulmonary or hepatic disease must be obtained at the time of disease progression on 
PIKTOR, prior to treatment with nab paclitaxel and cisplatin. If a research biopsy from a 
patient’s metastatic disease cannot be safely obtained, a skin biopsy is permitted.  
18. Assessments of other sites of disease must be performed only to confirm a CR.  
19. A toxicity assessment must be performed. 
20. Whole blood collection (40 mL) for germline exome sequencing studies at the time of 
disease progression (or off treatment) on PIKTOR. 
21. Patient diary assessment of PIKTOR dosing 
22. Patient diary assessment of in-home glucometer readings. NOTE: In-home glucose 
monitoring is not required on days when fasting glucose is measured in the clinic. See 
Section 11.9.1. 
11.5.3.2 
Assessments During Chemotherapy, Cycles 1 – 2 
The following assessments will be performed during chemotherapy prior to the start of each 
cycle, unless otherwise specified. A chemotherapy (nab paclitaxel plus cisplatin) Cycle is 
defined as 21 days. 
Note: Assessments will only be completed for the first 2 cycles of nab paclitaxel/cisplatin. 
For Cycles 3 – 6 data will be collected by chart review. 
There is a window (up to 4 calendar days prior to the scheduled time point) for 
assessments during the study. Any delay within this window is NOT a deviation. 
Assessments that are to be done on days when study drug is administered must be done 
prior to dosing as these assessments (CBC, CMP, assessment of response, etc) may 
determine whether or not drug is administered, or if a dose reduction is necessary, unless 
otherwise noted.  


 
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1. A brief medical history, to capture events that have occurred since the last cycle. Events 
that were not captured in the baseline complete medical history should be recorded on 
the AE page of the CRF. 
2. A brief physical examination, including vital signs and body weight. 
3. ECOG PS 
4. Assessment of concomitant medications 
5. A CBC with differential and platelet count  
6. A CMP  
7. EKG if clinically indicated. 
8. Tumor response by clinical assessment of the patient’s disease (ie, by physical 
examination)  
9. Radiological assessment of tumors (ie, chest and abdomen CT scan, radionuclide bone 
scan) as clinically indicated. The methods used for prestudy assessments should be used 
throughout the study. If possible, the same equipment should be used each time.  
10. Assessments of other sites of disease must be performed only to confirm a CR.  
11. A toxicity assessment must be performed. 
 
11.5.3.3 
Assessments During Chemotherapy, Cycles 3 – 6 
The following research data will be collected for research purposes. Clinic visits will 
continue per standard of care. 
1. Vital signs, body weight, and ECOG PS 
2. Assessment of concomitant medications 
3. CBC 
4. CMP 
5. Tumor response by clinical assessment of the patient’s disease 
6. Radiological assessment of tumors 
7. Toxicity assessment 
 
11.5.4  Off Treatment/End of Treatment Assessments 
This is a single assessment that will be performed within 30 days ± 2 days when patient 
finishes treatment or goes off treatment because of PD from nab paclitaxel plus cisplatin, or 
toxicity that places patients off treatment, or in cases of physician decision or where patient 
withdraws consent. Patients who withdraw consent may not want any further assessment; 
however, they should be encouraged to have these final assessments done. 
NOTE: End of treatment, or off treatment, is NOT considered off study or withdrawn from 
the study. Patients withdrawn under the criteria under Section 11.15 will not be followed.  
The following evaluation will be performed at this visit:  
1. A brief medical history should be done to capture events that have occurred since the last 
cycle. Events that were not captured in the baseline complete medical history should be 
recorded on the AE page of the CRF. 


 
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2. A brief physical examination, including vital signs and body weight. 
3. A CBC with differential and platelet count. 
4. A CMP   
5. Coagulation 
6. Fasting lipid profile 
7. Fasting serum glucose 
8. Urinalysis 
9. EKG 
10. A tumor clinical assessment of the patient’s disease (ie, by physical examination). 
11. A toxicity assessment. 
11.5.5  Follow Up Assessments 
The duration of patient participation in the study will be a maximum of 18 months, which is 
counted from the start of treatment, provided progressive disease on or post-nab paclitaxel 
plus cisplatin has not occurred. Follow-ups will be performed every 3 months for 1 year 
from the date of last treatment dose for patients who have not had progression of 
disease from chemotherapy.  
Note: Patients who die or withdraw consent are considered off study and no further 
information will be collected.  
1. Additional therapy  
2. Date and site of relapse or progression, including new primary malignancies (new 
primary malignancies must be reported to Takeda, see Section 14.2).  
3. Survival status  
4. Toxicities will be recorded for the first 30 days following the last study treatment. 
5. Clinical and radiological tumor assessment as per standard of care. 
11.5.6  Unscheduled Visits 
In special cases as judged by the Investigator, an additional visit to those scheduled can be 
performed. This visit will be recorded in the patient’s records and on the “Unscheduled 
visit” CRF pages.  
If the patient is discontinued prematurely, refer to Section 11.5.4 for required assessments. 
The resulting data should be documented on the appropriate CRF pages. If, at an 
unscheduled visit, the investigator determines the patient may remain on study drug, the visit 
assessments should be documented on the Unscheduled Visit CRF pages. 
NOTE: Assessments for an Unscheduled Visit are identical to Section 11.5.3. 
11.5.7  Blood Samples for Exome Sequencing 
Whole blood collection (40 mL) for exome sequencing studies will be obtained at baseline 
and at the time of disease progression (or off treatment) from PIKTOR. 
No information that identifies the patient will be given to any of the laboratories that will 


 
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analyze blood samples. Any material analyzed will be supplied with code number identifiers 
only, without the patient’s name or other identifying information. Access to the database 
which contains patient identifiers is limited to study investigators and project managers only 
and is safeguarded by a password protection system. Passwords are not shared. If research 
findings are published from this study, the research patient will not be identified by name. 
11.5.8  Biopsies 
Research biopsies will be obtained at the following time points (See Appendix VII for tissue 
collection and handling): 
• A minimum of four*14-gauge needle biopsy cores (or the largest core biopsy 
deemed safe) will be collected at baseline, prior to the initiation of PIKTOR. 
• A minimum of four* 14-gauge needle biopsy cores (or the largest core biopsy 
deemed safe) will be collected at the time of disease progression on PIKTOR, prior 
to treatment with nab paclitaxel and cisplatin. 
Tissue biopsies of a patient’s metastatic locoregional or pulmonary or hepatic disease will be 
analyzed by next generation sequencing (NGS) for mutations in DNA repair and PI3K 
pathways, as well as others. Remaining tissue will be frozen and/or formalin-fixed paraffin 
embedded (FFPE) for biomarker development. 
If a research biopsy from a patient’s metastatic disease cannot be safely obtained, a skin 
biopsy is permitted. 
11.6  Excluded Concomitant Medications and Procedures 
Based on in vitro drug metabolism studies, TAK-117 is primarily metabolized by CYP3A4 
(72%), with minor contributions from CYPs 1A2 (12%), 2C9 (9%), and 2C8 (6%); whereas, 
TAK-228 is metabolized by enzymes CYP2C19 (35%), CYP3A4 (28%), and 2C9 (28%). 
Consequently, induction of CYP3A, 2C19, and 2C9 enzymes by co-administered drugs can 
potentially result in decreased TAK-117 and TAK-228 exposures with the associated risk of 
decreased efficacy of TAK-117 and TAK-228. Conversely, inhibition of these enzymes can 
potentially result in increased TAK-117 and TAK-228 exposures and thus increase the risk 
for toxicity. Therefore, use of strong CYP3A4, CYP2C9, and CYP2C19 inhibitors and 
clinically significant enzyme inducers are not permitted within 1 week prior to 
administration of the first dose of TAK-228 and/or TAK-117. During the study, strong 
CYP3A4, CYP2C9, and CYP2C19 inhibitors and clinically significant enzyme inducers 
should only be administered with caution at the discretion of the investigator. 
There is potential for TAK-117 to affect the PK of breast cancer resistance protein (BCRP) 
substrates (eg, methotrexate, imatinib, topotecan, lapatinib, rosuvastatin, etc.) and organic 
cation transporter protein 1 or 2 (OCT1 or OCT2) substrates (eg, metformin, cimetidine, 
amantadine, famotidine, pindolol, etc.). If patients require treatment with medications that 
are known substrates of these transporters, then these agents should be administered with 
caution or alternative treatment options should be considered. It is recommended that 
patients requiring metformin for treatment of hyperglycemia resulting from TAK-228 + 
TAK-117 administration should begin treatment with the lowest effective dose of metformin 
and have their blood or serum glucose closely monitored. 


 
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The following medications and procedures are prohibited during the study: 
• Other investigational agents including mTOR, PI3Kinase and AKT inhibitors 
• Other anticancer therapies including chemotherapy, immunotherapy, 
radioimmunotherapy, and targeted agents. Palliative radiation may be administered 
after discussion with the Principal Investigator. 
• Systemic corticosteroids (either IV or oral steroids, excluding inhalers) during TAK-
228 and TAK-117 administration, unless necessary for treatment of TAK-228 related 
AE, ie, rash.  
• Enzyme-inducing anti-seizure drugs for patients with treated brain metastasis 
• Concomitant administration of any PPI is not permitted during the study 
administration of TAK-228 and TAK-117. 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. 
• Consumption of grapefruit or grapefruit juice is not permitted during the study 
administration of TAK-228 and TAK-117. 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 below restrictions in Section 11.7 that apply to the use of CYP3A4, CYP2C19 
and YP2C9 inhibitors and inducers, histamine H2 receptor antagonists, neutralizing 
antiacids, calcium and anti-gas preparations. 
• Herbal therapies or alternative therapies  
• Bisphosphonates or denosumab during the study administration of TAK-228 and 
TAK-117. 
11.7    
Permitted Concomitant Medications and Procedures  
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. 
Administration of neutralizing antacids and calcium preparations is permitted except from 
4 hours before until 2 hours after TAK-228 + TAK-117 administration. Some anti-gas 
preparations may also have antacid properties, and should also not be permitted from 
4 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 IV). Alternative treatments, if available, should be considered.  
All concomitant treatments, including blood and blood products, must be reported on the 


 
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source documentation and must be documented on the Concomitant Medications page of the 
CRF: 
 
• Blood and blood products 
• Antifungals 
• Prophylactic antibiotics 
• Growth factors 
• Premedications (ranitidine, 
diphenhydramine) 
 
All baseline concomitant medications should be collected in the CRF, as well as all OTC 
concomitant medications. All concomitant medications should be recorded on the source 
documentation. 
Other medications considered necessary for the safety and well-being of the patient may be 
administered at the discretion of the investigator. 
11.8    
Precautions and Restrictions  
No dietary restrictions will be imposed on study patients other than avoiding food or 
beverages containing the fruit or juice of grapefruits or Seville oranges within 7 days before 
first dose of study drug and throughout the study. Patients are required to fast for glucose 
monitoring, and refrain from eating or drinking for 2 hours before and 1 hour after each dose 
of TAK-228 and TAK-117. Patients will monitor their glucose levels at home daily while on 
TAK-228 and TAK-117 per Section 11.9.1.  
Patients who show evidence of hyperglycemia during the study should be encouraged to 
follow a low carbohydrate diet. 
Patients 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. 
Pregnancy  
It is not known what effects TAK-228 + TAK-117 have on human pregnancy or 
development of the embryo or fetus. Therefore, women participating in this study should 
avoid becoming pregnant, and men should avoid impregnating a female partner or donating 
sperm. Women of childbearing potential and men should use effective methods of 
contraception during and through 90 days after the last dose of study drug, as specified 
below. 
• Women must meet 1 of the following: 
o Postmenopausal for at least 1 year before the screening visit, OR 
o Surgically sterile, OR 
o If they are of childbearing potential, agree to practice 21 highly effective 
method of contraception and 1 additional effective (barrier) method, at the 
same time, from the time of signing the informed consent through 90 days (or 
longer, as mandated by local labeling [eg, USPI, SmPC, etc;]) after the last 
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o Agree to practice true abstinence, when this is in line with the preferred and 
usual lifestyle of the patient. (Periodic abstinence [eg, calendar, ovulation, 
symptothermal, postovulation methods], withdrawal, spermicides only, and 
lactational amenorrhea are not acceptable methods of contraception. Female 
and male condoms should not be used together.) 
11.9  Management of Clinical Events  
11.9.1 Management of Hyperglycemia 
On the basis of the clinical experience in TAK-228 trials, most episodes of hyperglycemia 
observed occurred within the first 60 days after initiation of treatment with TAK-228 and 
have been either Grade 1 or Grade 2, and have responded quickly to oral metformin. 
Hyperglycemia has not been dose-limiting since the institution of a standard regimen for 
early treatment of hyperglycemia. 
All patients developing hyperglycemia during the study should have their glucose closely 
monitored by study staff. The investigator may choose to continue close monitoring of 
patients who develop Grade 1 hyperglycemia (fasting glucose >ULN ≤160 mg/dL) or, 
alternatively, consider initiating treatment with an oral hypoglycemic agent, such as 
metformin. All patients with ≥Grade 2 hyperglycemia (fasting glucose >160 mg/dL) must be 
treated aggressively with oral hypoglycemic agents and/or insulin as clinically indicated. 
The investigator should consult an endocrinologist, if needed, to aid in optimizing the 
patient’s hyperglycemia treatment plan. 
It is recommended that patients be initially treated with a fast acting insulin sensitizer such 
as metformin at 500 mg orally QD, and titrate up to a maximum of 1000 mg orally 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 
patients. The dose of oral hypoglycemic agents should be adjusted in patients with renal 
insufficiency. In addition, patients should be encouraged to follow a low carbohydrate diet 
once hyperglycemia is first observed. 
If any fasting serum glucose reading performed at the site indicates hyperglycemia (>ULN 
or ≥110 mg/dL), the study staff should first confirm that the patient was fasting at the time 
of blood specimen collection (ie, nothing by mouth for at least 8 hours before collection). 
In-Home Daily Fasting Glucose Monitoring  
In addition to obtaining fasting glucose levels at the clinic visits as outlined in the Schedule 
of Events, all patients will be given a glucometer to monitor their daily fasting blood glucose 
(FBG) levels at home. The level should be collected daily, predose on study drug dosing 
days, and at approximately the same time each day. 
On Cycle 1 Day 1, the patient will be provided an in-home glucometer. Patients will be 
trained on proper use of the glucometer and instructed to collect a daily FBG level every 
morning (predose on dosing days), starting on Cycle 1 Day 2. Patients will be instructed to 
bring the glucometer and glucometer diary with them to each study visit so that the data 


 
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collected can be reviewed and recorded in the source documents. Investigators will be 
responsible for reviewing the home glucose monitoring logs for hyperglycemia. 
The patient will be instructed to contact the site immediately if the value is abnormal (ie, 
≥150 mg/dL) for further instructions on the management of their hyperglycemia. 
Hyperglycemia observed during home glucose monitoring should be confirmed in the clinic. 
If no irregularities in the fasting blood glucose level are observed during a minimum of 
2 consecutive months, then the frequency of in-home fasting blood glucose testing can be 
reduced to a minimum frequency of once weekly, depending on the investigator’s judgment 
and approval. Patients will continue to notify the investigator of fasting blood glucose levels 
that exceed 150 mg/dL and, if blood glucose levels are not well controlled, or if the patient 
requires either oral hypoglycemic agents or insulin to control blood glucose levels, then the 
frequency of in-home testing of FBG levels will be reinstated to daily. 
Guidance on study drug dose modification for patients with hyperglycemia is provided in 
the tables below. 
Table 6. 
Management of Hyperglycemia 
Grade Description 
Treatment 
Dose Modification 
1 
Fasting blood 
glucose:  FGG 
>ULN to 160 
mg/dL 
• Continue close monitoring of 
blood sugar. 
• Initiate oral hypoglycemic 
agent. 
None 
2 
FBG>160 to 250 
mg/dL 
• Initiate oral hypoglycemic agent 
and/or insulin if not well 
controlled on oral agent. 
None 
≥3 
FBG>250 mg/dL 
• Initiate oral hypoglycemic agent 
and/or insulin. 
Hold TAK-228 and TAK-
117 until ≤Grade 2.  
Resume TAK-228 and 
TAK-117 based on timing 
of recovery after maximal 
treatment: 
• ≤1 week: resume TAK-
228 and TAK-117 at 
same dose and schedule. 
• >1 but ≤2 weeks: reduce 
TAK-228 and TAK-117 
by 1 dose level 
• >2 weeks: discontinue 
patient from the study. 


 
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Table 6. 
Management of Hyperglycemia 
Grade Description 
Treatment 
Dose Modification 
Prevention/Prophylaxis: 
• 
Follow fasting glucose levels during clinic visits. 
• 
Monitor home glucometer test results. 
• 
Check HbA1c levels every 3 months during therapy. 
• 
Recommend life-style modifications, as appropriate (balanced diet, limited alcohol 
consumption, increased physical activity). 
• 
Most episodes of Grade 1 or 2 hyperglycemia respond quickly to oral metformin. Early 
initiation of therapy at the lowest therapeutic dose is recommended to prevent higher grade 
hyperglycemia. 
• 
Fasting blood glucose levels ≥150 mg/dL by glucometer should be followed by closer 
monitoring of serum glucose and possible intervention.  
HbA1c=glycosylated hemoglobin, ULN=upper limit of normal.  
11.9.2      Management of Hyperlipidemia 
Guidance on study drug dose modification for patients with hyperlipidemia is provided 
below. 
Table 7. 
Management of Hyperlipidemia 
Grade 
Description 
Treatment 
Dose Modification 
1 
Cholesterol >ULN to 300 mg/dL 
Triglycerides >150 to 300 mg/dL 
None 
None 
2 
Cholesterol >300 to 400 mg/dL 
 
 
Triglycerides >300 to 500 mg/dL 
• 
Treat hyperlipidemia 
according to standard 
guidelines. 
• 
Triglycerides 
≥500 mg/dL should be 
treated urgently, due to 
risk of pancreatitis. 
• 
Maintain dose, if 
tolerable. 
• 
If toxicity becomes 
intolerable, interrupt 
TAK-228 and TAK-117 
until recovery to ≤Grade 
1. Re-initiate TAK-228 
+TAK-117 at the same 
dose level 
3 
Cholesterol >400 to 500 mg/dL 
 
Triglycerides >500 to 
1000 mg/dL 
Same as for Grade 2. 
Hold TAK-228 and TAK-
117 until recovery to ≤Grade 
1, then reinitiate TAK-228 
and TAK-117 at a dose 
reduced by 1 level  
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 alcohol consumption, increase physical 
activity) 
ULN=upper limit of normal 
11.9.3      Management of Oral Mucositis 
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Table 8. 
Management of Oral Mucositis 
Grade 
Description 
Treatment 
Dose Modification 
1 
Asymptomatic or mild 
symptoms. 
• 
Nonalcoholic mouth wash, or 
0.9% salt water rinse. 
• 
Consider topical 
corticosteroids at earliest signs 
of mucositis. 
None 
2 
Moderate pain, not 
interfering with oral 
intake. 
Modified diet indicated. 
• 
Topical analgesic mouth 
treatments. 
• 
Topical corticosteroids. 
• 
Initiate antiviral or antifungal 
therapy, if indicated. 
• 
Maintain TAK-228 and 
TAK-117 dose if 
tolerable 
• 
Hold only TAK-228 and 
TAK-117 if intolerable 
until recovery to ≤Grade 
1, then restart at same 
dose. 
3 
Severe pain, interfering 
with oral intake. 
• 
Same as for Grade 2. 
• 
Consider intralesional 
corticosteroids. 
• 
Hold TAK-228 and 
TAK-117 until recovery 
to ≤Grade 1, then restart 
TAK-228 and TAK-117 
at a dose reduced by 
1 level 
4 
Life-threatening 
consequences. 
• 
Same as for Grade 2 
• 
Consider intra-lesional 
corticosteroids 
• 
Stop TAK-228 and TAK-
117 and discontinue 
patient from the study 
Prevention/Prophylaxis: 
• 
Initiation of a nonalcoholic mouth wash, or 0.9% salt water rinses 4 to 6 times daily is strongly 
recommended at the 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. 
 
11.9.4      Management of Rash 
Guidance on study drug dose modification for patients with rash is provided below. 
 
Table 9. 
Management of Rash 
Grade 
Description 
Treatment 
Dose Modification 
≤2 
Macules/papules covering 
≤30% body surface area 
with or without 
symptoms. 
Consider treatment with topical 
steroid cream/ointment and/or 
oral anti-histamines or 
antibiotics. 
None 


 
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3 
Macules/papules covering 
30% body surface area 
with or without 
symptoms. 
Consider treatment with topical 
steroid cream/ointment, oral 
anti-histamines, oral antibiotics, 
and/or pulsed steroids. 
Hold TAK-228 and TAK-117 
until ≤Grade 2 
 
Resume TAK-228 and TAK-117 
based on timing of recovery: 
• 
≤3 weeks: reduce TAK-228 
and TAK-117 by 1 dose level  
• 
>3 weeks: stop TAK-228 and 
TAK-117 and discontinue 
patient from the study 
4 
Rash 
acneifom/papulopustular 
with papules and/or 
pustules covering any % 
body surface area, which 
may or may not be 
associated with symptoms 
of pruritus or tenderness, 
and are associated with 
extensive superinfection 
with intravenous (IV) 
antibiotics indicated; life 
threatening consequences 
(NCI CTCAE 
Version 4.03, effective 
date 14 June 2010). 
 
 
Permanently discontinue study 
treatment, unless they derive 
clinical benefit, in which case they 
may be retreated at a reduced dose 
level after recover to  Grade 1 
severity 
Prevention/Prophylaxis: 
• 
Rash should be managed aggressively. The investigator should consider consulting a dermatologist or 
other specialist, if needed. 
• 
A skin biopsy at the site of rash should be considered as soon as possible after the initial episode. 
11.9.5      Management of Nausea/Vomiting 
Guidance for patients with nausea and/or vomiting is provided in the table below. 
 
Table 10. 
Management of Nausea/Vomiting  
Grade 
Description 
Treatment 
Dose Modification 
≤2 
Loss of appetite with or 
without decreased oral intake;  
1 to 5 episodes of vomiting 
within 24 hours. 
• 
Maximize anti-emetic 
therapy. 
• 
Consider IV fluid 
hydration. 
None 
≥3 
Inadequate oral intake;  
≥6 episodes of vomiting 
within 24 hours. 
• 
Maximize anti-emetic 
therapy. 
• 
Initiate tube feeding, IVF 
or TPN. 
If experienced for ≤72 hours, 
hold TAK-228 and TAK-117 
until ≤Grade 1, then resume 
TAK-228 and TAK-117 
without dose modification. If 
experienced for >72 hours 
despite optimal therapy, hold 
TAK-228 and TAK-117 until ≤ 
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with the dose of TAK-228 and 
TAK-117 reduced by 1 level. 
Prevention/Prophylaxis: 
Prophylactic use of anti-emetic, antinausea, and antidiarrheal medications are encouraged and may be used 
before each TAK-228 dosing as needed throughout the study. 
IV=intravenous, IVF=intravenous fluids, TPN=total parental nutrition. 
 
11.9.6      Management of Cardiac Abnormalities 
Management of Patients with Possible Cardiac Instability 
For patients showing signs of cardiac instability after TAK-228 and TAK-117 
administration, additional monitoring onsite before clinic discharge should be considered. 
Management of Patients with Left Ventricular Dysfunction 
Guidance for TAK-228 and TAK-117 dose adjustments for patients with left ventricular 
dysfunction is provided below. 
 
Table 11. 
Management of Left Ventricular Dysfunction  
Grade 
Description 
Dose Modification 
1 
Asymptomatic decline in: 
LVEF >15% from baseline values, OR 
LVEF >10% to 15% from baseline values and 
is below institution’s LLN. 
No change; continue TAK-228 and TAK-117 
at the same dose and schedule 
2 
Symptomatic cardiac dysfunction/congestive 
heart failure. 
Discontinue treatment. 
LLN=lower limit of normal, LVEF=left ventricular ejection fraction.  
 
11.9.7      Management of Patients with QTc Prolongation 
Guidance for TAK-228 and TAK-117 dose adjustments for patients exhibiting a prolonged 
QTc interval is provided below. 
 
Table 12. 
Management of QTc Prolongation  
Grade 
Description 
Treatment 
Dose Modification 
2 
480 msec QTc 
501 msec 
Evaluate for other possible causes (eg, 
electrolyte disturbance, concomitant 
medication, etc). 
None; continue TAK-228 and TAK-117 
at the same dose and schedule. 


 
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Table 12. 
Management of QTc Prolongation  
Grade 
Description 
Treatment 
Dose Modification 
3 
QTc 501 msec 
Evaluate for other possible causes (eg, 
electrolyte disturbance, concomitant 
medication).(a) 
Consider a formal consult by a 
cardiologist; 
Notify the study doctor; 
Additional ECGs may be performed at 
intervals that the treating physician 
deems clinically appropriate until 
repeated QTc measurements fall or are 
below the threshold interval that 
triggered the repeat measurement. 
Hold TAK-228 and TAK-117 
The decision whether to reinitiate TAK-
228 and TAK-117 with or without dose 
reduction and additional monitoring in 
those patients who had asymptomatic 
prolonged QTc ≥501 msec (Grade 3) 
that has reverted to an acceptable 
interval, have previously tolerated 
TAK-228 and TAK-117, and appear to 
have benefitted from treatment with 
either disease control or response, will 
be agreed to by the investigator on a 
case-by-case basis 
Patients who experience persistent 
symptomatic Grade 3 or Grade 4 QTc 
prolongation without another cause 
should permanently discontinue study 
treatment.  
ECG=electrocardiogram, IV=intravenous, msec=milliseconds, QTc=QT interval corrected for heart rate. 
(a) A list of medications known to prolong QTc can be found at https://www.crediblemeds.org/new-drug-list/ 
 
 
11.9.8      Management of Asthenia, Weakness and Fatigue 
Guidance on dose adjustment for patients with other nonhematologic toxicities is provided 
below. 
 
Table 13. 
Management of Asthenia, Weakness, and Fatigue  
Grade 
Description 
Treatment 
Dose Modification 
1 
Mild; asymptomatic or mild 
symptoms; clinical or 
diagnostic observations only; 
intervention not indicated. 
Initiate appropriate medical 
therapy and monitor. 
If tolerable, then no adjustment is 
required. 
2 
Moderate; minimal, local or 
noninvasive intervention 
indicated. 
Initiate appropriate medical 
therapy and monitor. 
• 
If tolerable, no adjustment 
required. 
• 
If toxicity becomes 
intolerable, hold TAK-228 
and TAK-117 until recovery 
to ≤Grade 1, then reinitiate at 
same dose.  
≥ 3 
Severe or medically 
significant but not 
immediately life-threatening; 
hospitalization or 
prolongation of 
hospitalization indicated 
 
Hold TAK-228 and TAK-117  
until recovery to ≤ Grade 1. 
Reinitiate TAK-228 and TAK-117 
at dose reduced by 1 level.  
Patients who develop Grade 4 
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Table 13. 
Management of Asthenia, Weakness, and Fatigue  
Grade 
Description 
Treatment 
Dose Modification 
values) should permanently 
discontinue study treatment, 
unless they derive clinical benefit, 
in which case they may be 
retreated at a reduced dose level 
after recovery to ≤ Grade 1 
severity. 
11.9.9      Management of Aspartate Aminotransferase/Alanine Aminotransferase 
Elevations 
Guidance on dose adjustment for patients with AST/ALT elevations is provided below. 
 
Table 14. 
Management of Aspartate Aminotransferase/Alanine 
Aminotransferase Elevations  
Grade 
Description 
Treatment 
Dose Modification 
1 
>ULN to 3ULN 
None 
None 
2 
Asymptomatic with levels 
3 to 5ULN 
• 
Closely monitor LFTs at 
least weekly or more 
frequently as indicated. 
• 
Assess patient for other 
causes of transaminitis (eg, 
past medical history, 
concomitant medications). 
None 
3 
>5 to 20ULN; >5ULN for 
>2 weeks 
Same as for Grade 2. 
Hold TAK-228 and TAK-117 
until ≤Grade 1; Restart TAK-
228 and TAK-117 at the same 
dose. Permanently discontinue 
study treatment if in 
combination with Grade 2 total 
bilirubin elevation when 
alternative causes cannot be 
identified (ie, Hy’s Law); 
4 
>20ULN 
Same as for Grade 2. 
Stop TAK-228 and TAK-117 
and discontinue patient from the 
study. Permanently discontinue 
study treatment if in 
combination with Grade 2 total 
bilirubin elevation when 
alternative causes cannot be 
identified (ie, Hy’s Law). 
Prevention/Prophylaxis: 
Ensure proper screening of patients for study participation. 
LFTs=liver function tests, ULN=upper limit of normal. 
11.9.10      Management of Non-infectious Pneumonitis 
Guidance for the management of pneumonitis is provided below. 


 
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Table 15. 
Management of Non-infectious Pneumonitis  
Grade 
Description  
Treatment 
TAK-228 Dose 
Modification 
1 
Asymptomatic: Radiographic findings 
only. 
Rule out infection and 
closely monitor. 
None 
2 
Symptomatic: 
Not interfering with activities of 
daily living. 
Rule out infection and 
consider treatment with 
corticosteroids until 
symptoms improve to 
≤Grade 1. 
Hold TAK-228 and 
TAK-117 
• When symptoms 
≤Grade 1, reinitiate 
TAK-228 and TAK-
117 at a dose 
reduced by 1 level. 
If no recovery 
within 4 weeks, then 
discontinue TAK-
228 and TAK-117.  
3 
Symptomatic: 
Interfering with activities of daily 
living; 
Requires administration of oxygen. 
Rule out infection and 
consider treatment with 
corticosteroids until 
symptoms improve to 
≤Grade 1. 
Hold TAK-228 and 
TAK-117 until 
symptoms resolve to 
≤Grade 1.  
• Consider reinitiating 
TAK-228 and TAK-
117 at a dose 
reduced by 1 level 
• If toxicity recurs at 
Grade 3, discontinue 
TAK-228 and TAK-
117. 
4 
Life-threatening: 
Ventilatory support indicated. 
Rule out infection and 
consider treatment with 
corticosteroids. 
Discontinue TAK-228 
and TAK-117. 
11.10 
Description of Investigational Agents 
TAK-228 will be supplied as capsules for oral administration. The study drug is available in 
3 dose strengths, 1 mg, 3 mg, and 5 mg, each containing 1 mg, 3 mg, and 5 mg of TAK-228, 
respectively, in addition to the following inactive ingredients: microcrystalline cellulose 
(solid filler/diluents), magnesium stearate (lubricant), 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: 
• TAK-228 capsules, 1 mg - white opaque color 
• TAK-228 capsules, 3 mg – orange opaque color; and/or 
• TAK-228 capsules, 5 mg – grey opaque color  
TAK-117 will be supplied as 100 mg capsules for oral administration. Each 100 mg capsule 
contains 100 mg of MLN1117 and the following inactive ingredients: hard gelatin capsule 
and small amount of colloidal silicon dioxide. 
Refer to the MLN0128 + MLN1117 (TAK-228 + TAK-117) IB for full details.(43) 


 
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11.11 
Preparation, Reconstitution, and Dispensing 
TAK-228 and TAK-117 study drugs will be provided in labeled bottles in accordance with 
all applicable regulations. Materials provided by the sponsor should be dispensed to patients 
with clear administration instructions from the investigator. 
TAK-228 and TAK-117 are anticancer drugs and, as with other potentially toxic 
compounds, caution should be exercised when handling TAK-228 and TAK-117 capsules. 
11.12 
Packaging and Labeling 
TAK-228 and TAK-117 will be provided by Millennium and will be handled at the 
investigative site as open-label material. Sites must store according to the labeled conditions. 
TAK-228 and TAK-117 will be provided in 30-ct, 60-cc high density polyethylene (HDPE) 
bottles with polypropylene, child-resistant caps and induction seal. 
TAK-228 and TAK-117 are packaged and labeled in accordance with all applicable 
regulations. 
11.13 
Storage, Handling, and Accountability 
Upon receipt at the investigative site, drug should be stored in the original bottles until use 
and stored at room temperature from 15°C to 30°C (59°F to 86°F). All temperature 
excursions will be reported for assessment and authorization for continued use. All 
investigational supplies must be stored in a secure area with controlled access and will be 
stored in original packaging. All drug supplies should be used before the retest expiry date. 
Because TAK-228 and TAK-117 are investigational agents, they 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 (e.g., from a broken 
capsule), the skin should be washed immediately with soap and copious amounts of water 
for at least 15 minutes. In case of contact with the eyes, copious amounts of water should be 
used to flush the eyes for at least 15 minutes. Medical personnel should be notified. 
Patients will receive instructions for home storage and administration of TAK-228 and 
TAK-117. 
Accountability for TAK-228 and TAK-117 at all study sites is the responsibility of the 
sponsor-investigator. 
11.14    
 Study Compliance 
Study drug will be administered or dispensed only to eligible patients under the supervision 
of the investigator or identified sub-investigator(s).  The appropriate study personnel will 
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11.15   
Termination of Treatment and/or Study Participation 
Patients will be informed that they have the right to withdraw from the study at any time for 
any reason, without prejudice to their medical care, and will be considered “off study”. After 
EOT assessments are completed at withdrawal, no further follow up will be completed. 
Patients will be withdrawn from the study if any of the following occur:  
1. Withdrawal of consent (patient will not be contacted and no further information will be 
collected). If the patient withdraws consent, then no additional data will be collected 
without his/her explicit consent; all data collected prior to withdrawal of consent may 
be used in the data analysis.  
2.  Termination of study by Baylor IRB or Principal Investigators  
3.  Disease progression from nab paclitaxel plus cisplatin treatment  
4. 
Intolerable toxicity 
5. 
An intercurrent illness, which would in the judgment of the Investigator, affect 
assessments of clinical status to a significant degree or require discontinuation of study 
treatment. 
6. 
Non-protocol therapy (chemotherapy, radiotherapy, hormonal therapy, 
immunotherapy, or surgery) that is administered during study  
7. 
Noncompliance with protocol or treatment 
8. 
Pregnancy 
9. Lost to follow-up (3 attempts should be documented in the patient’s source document 
before the site considers the patient as LFU.) 
The date of and reason for discontinuation must be noted on the Case Report Form (CRF). 
Every effort should be made to complete the appropriate assessments. 
If the patient is withdrawn for any reason, the end of study assessments must be completed. 
Patients who withdraw from the study treatment due to intolerable toxicity will still be 
followed for outcome and toxicity, per protocol.  
Patients must still be followed for adverse events (AEs) for 30 calendar days after their last 
dose of study drug. All new AEs occurring during this period must be reported and followed 
until resolution, or after 30 days (whichever comes first), unless, in the opinion of the 
investigator, these values are not likely to improve because of the underlying disease. In this 
case, the investigators must record his or her reasoning for this decision in the patients’ 
medical records and as a comment on the CRF. 
All patients who have CTCAE grade 3 or 4 laboratory abnormalities at the time of 
withdrawal must be followed until the laboratory values have returned to grade 1 or 2, or 
until 30 days after the date of withdrawal (whichever comes first), unless it is, in the opinion 
of the investigator, not likely that these values are to improve because of the underlying 
disease. In this case, the investigator must record his or her reasoning for making this 
decision in the patients’ medical records and as a comment on the CRF. 


 
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12.        
EFFICACY ASSESSMENTS (SOLID TUMOR) 
12.1    
Response Criteria 
All efficacy assessments will be investigator assessments of response, time to response, and 
duration of response. Investigator will determine complete response (CR), partial response 
(PR), stable disease (SD), or progression of disease (PD).  
 
13.  
 
STATISTICAL AND QUANTITATIVE ANALYSES 
13.1    
Statistical Methods 
Ten patients with metTNBC will be enrolled in this proof of concept Phase II study and will 
be treated with TAK-228/TAK-117 followed by cisplatin plus nab paclitaxel at disease 
progression on PIKTOR. If zero of 10 patients have an objective response with TAK-
228/TAK-117, enrollment will be stopped. If at least 1 of 10 patients has an objective 
response with this combination, an additional 10 patients will be enrolled on study. With a 
sample size of 20 patients, there is an 80% chance of observing 4 or more responses if the 
true response rate is at least 20%. The complete response rate and duration of response will 
also be assessed to determine if TAK-228/TAK-117 followed by cisplatin/nab paclitaxel 
will produce any exceptional responses of at least 12 months duration following cessation of 
chemotherapy. 
13.1.1     Determination of Sample Size 
Twenty patients will be enrolled over 12-18 months. 
Twenty patients provides 80% power to reject the null hypothesis that more than 20% of 
patients will develop toxicity with the combination that leads to treatment cessation, or delay 
in treatment of more than 4 weeks. 
13.1.2    Populations for Analysis 
Intent-To-Treat (ITT) Population: Includes all patients registered on the study (eligible 
and ineligible). This population will be included in overall patient listings, in summary 
tables of patient demographics and baseline disease characteristics, and also in the list of 
treatment discontinuations after enrollment. 
Evaluable Population: Includes all eligible patients who meet the protocol-specified 
efficacy analyses requirements and who have received at least 1 dosing of PIKTOR therapy. 
This population will comprise those patients who will be assessed for pathologic response. 
Early discontinuation of treatment (in Cycles 1-2), secondary to toxicity, will be considered 
a treatment failure. If death occurs before the completion of 1 cycle, the patient will be 
reported as evaluable, early death, but deemed not evaluable for response. 
Safety Population: Includes all patients (eligible and ineligible) who receive at least 
1 dosing of PIKTOR therapy. This safety population will also be used for the summaries and 
analysis of all safety parameters (drug exposure, tables of adverse events information, 
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that occur >30 days after the administration of treatment will not be reported or analyzed. 
13.1.3    Patient Characteristics and Disposition 
Patient characteristics including demographics and pretreatment characteristics, breast mass 
and axillary lymph node size, staging evaluation at baseline, medical history, and family 
history will be summarized. Descriptive statistics including sample size, mean, standard 
deviation, median, and minimum and maximum values will be presented for continuous 
variables. Frequency distributions will be presented for categorical variables. 
Patient disposition including the number of patients enrolled, completed, and discontinued 
from the study will be summarized overall and by study site. The reasons for discontinuation 
will also be summarized, and patients who discontinued will be listed. 
13.1.4   Hypothesis and Endpoints 
The hypothesis of this proof of concept Phase II trial is that administration of the oral 
combination of TAK-228 and TAK-117 will inhibit NHEJ in metastatic TNBC leading at 
the time of disease progression to metastases that are HR-deficient and sensitive to cisplatin 
plus nab paclitaxel therapy.  
This is an exploratory and descriptive clinical trial in which the primary objective is to 
assess the objective response rate associated with sequential treatment with the oral 
combination of TAK-228 and TAK-117 (PIKTOR) followed, upon progression on PIKTOR, 
by cisplatin plus nab paclitaxel in metastatic triple negative breast cancer (metTNBC) 
patients. 
The secondary objectives of this trial are to assess the safety, duration of response; assess 
the metastatic TNBC tissues for homologous recombination proficiency and deficiency; and 
collect frozen and/or formalin-fixed paraffin embedded (FFPE) tissue for biomarker 
development. 
13.1.5   Biopsies 
Tissue biopsies of a patient’s metastatic locoregional or pulmonary or hepatic disease will be 
analyzed by next generation sequencing (NGS) for mutations in DNA repair and PI3K 
pathways, as well as others. Remaining tissue will be frozen and/or formalin-fixed paraffin 
embedded (FFPE) for biomarker development. 
If a research biopsy from a patient’s metastatic disease cannot be safely obtained, a skin 
biopsy is permitted. 
14.    ADVERSE EVENTS   
14.1    
Definitions 
14.1.1    Adverse Event Definition 
Adverse event (AE) means any untoward medical occurrence in a patient or subject 
administered a medicinal product; the untoward medical occurrence does not necessarily 
have a causal relationship with this treatment.  An AE can therefore be any unfavorable and 


 
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unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product whether or not it is related to 
the medicinal product.  This includes any newly occurring event, or a previous condition 
that has increased in severity or frequency since the administration of study drug. 
An abnormal laboratory value will not be assessed as an AE unless that value leads to 
discontinuation or delay in treatment, dose modification, therapeutic intervention, or is 
considered by the investigator to be a clinically significant change from baseline.   
14.1.2    Adverse Drug Reaction 
Adverse event (AE) means any untoward medical occurrence in a patient or subject 
administered a medicinal product; the untoward medical occurrence does not necessarily 
have a causal relationship with this treatment.  An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product whether or not it is related to 
the medicinal product.  This includes any newly occurring event, or a previous condition 
that has increased in severity or frequency since the administration of study drug. 
An abnormal laboratory value will not be assessed as an AE unless that value leads to 
discontinuation or delay in treatment, dose modification, therapeutic intervention, or is 
considered by the investigator to be a clinically significant change from baseline. 
14.1.3    Serious Adverse Event Definition 
Serious AE (SAE) means any untoward medical occurrence that at any dose: 
• Results in death (NOTE: Any death from any cause while a patient is receiving 
treatment on this protocol, or  30 days following the last dose of protocol treatment 
must be reported.) 
• Is life-threatening (refers to an AE in which the patient was at risk of death at the 
time of the event.  It does not refer to an event which hypothetically might have 
caused death if it were more severe). 
• Requires inpatient hospitalization or prolongation of an existing hospitalization 
(see clarification in the paragraph below on planned hospitalizations). 
• Results in persistent or significant disability or incapacity. (Disability is defined 
as a substantial disruption of a person’s ability to conduct normal life functions). 
• Is a congenital anomaly/birth defect. 
• Is a medically important event.  This refers to an AE that may not result in death, 
be immediately life threatening, or require hospitalization, but may be considered 
serious when, based on appropriate medical judgment, may jeopardize the patient, 
require medical or surgical intervention to prevent 1 of the outcomes listed above, or 
involves suspected transmission via a medicinal product of an infectious agent.   
Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do 
not result in inpatient hospitalization, or the development of drug dependency or 
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Transmissible Spongiform Encephalopathy), pathogenic or nonpathogenic, is 
considered an infectious agent.   
Clarification should be made between a serious AE (SAE) and an AE that is considered 
severe in intensity (Grade 3 or 4), because the terms serious and severe are NOT 
synonymous.  The general term severe is often used to describe the intensity (severity) of a 
specific event; the event itself, however, may be of relatively minor medical significance 
(such as a Grade 3 headache).  This is NOT the same as serious, which is based on 
patient/event outcome or action criteria described above, and is usually associated with 
events that pose a threat to a patient’s life or ability to function. A severe AE (Grade 3 or 4) 
does not necessarily need to be considered serious. For example, a white blood cell count of 
1000/mm3 to less than 2000 is considered Grade 3 (severe) but may not be considered 
serious. Seriousness (not intensity) serves as a guide for defining regulatory reporting 
obligations. 
14.2    
Procedures for Reporting Serious Adverse Events 
Adverse Events may be spontaneously identified 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.   
Adverse Events which are serious must be reported to Takeda Pharmacovigilance (or 
designee) from the time of consent up to and including 30 days after administration of the 
last dose of PIKTOR. Any SAE that occurs at any time after completion of PIKTOR 
treatment or after the designated follow-up period that the sponsor-investigator and/or sub-
investigator considers to be related to any study drug must be reported to Takeda 
Pharmacovigilance (or designee).   
In addition, new primary malignancies that occur during the follow-up periods must be 
reported, regardless of causality to study regimen, for a minimum of 3 years after the last 
dose of the investigational product, starting from the first dose of study drug. All new cases 
of primary malignancy must be reported to Takeda 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 (ie, surgery was performed earlier or 
later than planned).  All SAEs should be monitored until they are resolved or are clearly 
determined to be due to a patient’s stable or chronic condition or intercurrent illness (es). 
Since this is an investigator-initiated study, the principal investigator Joyce O'Shaughnessy, 
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 EC or IRB.    
Regardless of expectedness or causality, all SAEs must also be reported in English to 
Takeda Pharmacovigilance or designee: 
Fatal and Life Threatening SAEs within 24 hours of the sponsor-investigator’s 
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All other serious (non-fatal/non life threatening) events within 4 calendar days of 
the sponsor-investigator’s observation or awareness of the event 
The Sponsor will send all SAE reports to Takeda Pharmacovigilance (or designee) within 
24 hours but no later than 4 calendar days as per any agreements. 
See below for contact information for the reporting of SAEs to Takeda Pharmacovigilance. 
The sponsor-investigator must fax or email the SAE Form per the timelines above. A sample 
of an SAE Form will be provided. 
The SAE report must include at minimum: 
• Event term(s) 
• Serious criteria 
• Intensity of the event(s): Sponsor-investigator’s or sub-investigator’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 Takeda Pharmacovigilance (or 
designee).   
In the event that this is a multisite study, the sponsor-investigator is responsible to ensure 
that the SAE reports are sent to Takeda Pharmacovigilance (or designee) from all sites 
participating in the study.  Sub-investigators must report all SAEs to the sponsor-
investigator so that the sponsor-investigator can meet his/her foregoing reporting obligations 
to the required regulatory agencies and to Takeda Pharmacovigilance, unless otherwise 
agreed between the sponsor-investigator and sub-investigator(s).   
Relationship to all study drugs for each SAE will be determined by the investigator or sub-
investigator by responding yes or no to the question: Is there a reasonable possibility that the 
AE is associated with the study drug(s)? 
 
 
 
 
 
 
 
 
 
US and Canada 
Toll-Free Fax #: 1-800-963-6290 
E-mail: takedaoncocases@cognizant.com 
 
All other countries (Rest of World) 
Fax #: 1 202 315 3560 
E-mail: takedaoncocases@cognizant.com 
 


 
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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 
14.3    
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 Takeda 
Pharmacovigilance or designee immediately (see Section 14.2).  The pregnancy must be 
followed for the final pregnancy outcome (eg, delivery, still birth, miscarriage) and Takeda 
Pharmacovigilance or designee will request this information from the sponsor-investigator. 
If a female partner of a male patient becomes pregnant during the male patient’s 
participation in this study, the sponsor-investigator must also immediately fax a completed 
Pregnancy Form to the Takeda Pharmacovigilance or designee (see Section 14.2).  Every 
effort should be made to follow the pregnancy for the final pregnancy outcome. 
15.    ADMINISTRATIVE REQUIREMENTS 
15.1    
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 Takeda (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 
Takeda Quality representative. 
A medication error is a preventable event that involves an identifiable patient and that leads 
to inappropriate medication use, which may result in patient harm.  While overdoses and 
underdoses constitute medication errors, doses missed inadvertently by a patient do not.  
Individuals who identify a potential medication error situation should immediately contact 
Takeda (see below) and report the event.  
 
For Product Complaints or Medication Errors, call 
 
For ADCETRIS or PIPELINE Products: 
Phone: 1-844-ONC-TKDA (1-844-662-8532) 
Email: GlobalOncologyMedInfo@takeda.com 
Fax: 1-800-881-6092, Hours Mon – Fri, 9 a.m. – 7 p.m. ET 
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 Takeda Pharmacovigilance (refer to 
Section 14.2). 
 
 


 
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16.  
REFERENCES  
1. Breast Cancer: Prevention and Control. World Health Organization. Available at: 
http://www.who.int/cancer/detection/breastcancer/en/index1.html. Accessed May 
25,2015. 
2. NCCN Clinical Practice Guidelines in Oncology: Breast Cancer. V2.2015. National 
Comprehensive Cancer Network Web site. 
http://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Accessed May 25, 
2015. 
3. Ma CX, Luo J, and Ellis MJ. Molecular profiling of triple negative breast cancer. 
Breast Dis. 2010;32:73-84. 
4. Hudis CA, and Gianni L. Triple-negative breast cancer: an unmet medical need. 
Oncologist. 2011;16(Suppl 1):1-11. 
5. Prat A, et al. Molecular features of the basal-like breast cancer subtype based on 
BRCA1 mutation status. Breast Cancer Res Treat 14:185-191, 2014. 
6. Helleday T. Homologous recombination in cancer development, treatment and 
development of drug resistance. Carcinogenesis 31:955-960, 2010.  
7. Tobin L, et al. Targeting abnormal DNA repair in therapy-resistant breast cancers.  
Mol Cancer Res 10: 96-107, 2012. 
8. Brand TM, et al. Nuclear EGFR as a molecular target in cancer. Radiother Oncology 
108:1-18, 2014 
9. Burga LN, et al. Loss of BRCA1 leads to an increase in epidermal growth factor 
receptor expression in mammary epithelial cells, and epidermal growth factor 
receptor inhibition prevents estrogen receptor-negative cancers in BRCA1-mutant 
mice. Breast Cancer Res 13:R30, 2011. 
10. Gil del Alcazar CR, et al. Inhibition of DNA double-strand break repair by the dual 
PI3K/mTOR inhibitor NVP-BEZ-235 as a strategy for radiosensitization of 
glioblastoma. Clin Ca Res 20:1235, 2014. 
11. Bendell, J, et al. A phase I study of the sachet formulation of the oral dual 
PI3K/mTOR inhibitor BEZ-235 given twice daily (BID) in patients with advanced 
solid tumors. Invest New Drugs 33:463, 2015. 
12. Musa F, Alard A, David-West G, et al. Dual mTORC1/2 inhibition as a novel 
strategy for the resensitization and treatment of platinum-resistant ovarian cancer. 
Mol Cancer Ther 15(7):1557-1567, 2016. 
13. Ibrahim NK, Desai N, Legha S, et al: Phase I and Pharmacokinetic Study of ABI-
007, a Cremophor-free, Protein-stabilized, Nanoparticle Formulation of Paclitaxel. 
Clin Cancer Research. 2002 May; 8: 1038-1044. 
14. Ibrahim NK, Samuels B, Page R, et al: Multicenter Phase II Trial of ABI-007, an 
Albumin-Bound Paclitaxel, in Women with Metastatic Breast Cancer. J Clin Oncol. 
23:6019-6026,2005. 
15. Abraxane Investigator’s Brochure, July 2015. 


 
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16. Gradishar WJ, Tjulandin S, Davidson N, et al. Phase III Trial of Nanoparticle 
Albumin-Bound Paclitaxel Compared with Polyethylated Castor-Oil-Based 
Paclitaxel in Women with Metastatic Breast Cancer. J Clin Oncol. 23:7794-7803, 
2005. 
17. Sun S, Tang L, Zhang J, et al. Cisplatin improves antitumor activity of weekly nab-
paclitaxel in patients with metastatic breast cancer. Int J Nanomedicine. 
2014;9:1443-52. 
18. Yardley D, Coleman R, Conte P, et al. nab-paclitaxel + carboplatin or gemcitabine 
vs gemcitabine/carboplatin as first-line treatment for patients with triple-negative 
metastatic breast cancer: Results from the randomized phase 2 portion of the tnAcity 
trialCancer Res 77(4 Suppl):Abstract nr P5-15-03, 2017. 
19. O’Shaughnessy, J, Espina V, Cherni I, et al. Dual inhibition of DNA double strand 
break repair and PI3K with BEZ-235 to sensitize refractory metastatic triple negative 
breast cancer to cisplatin/nab paclitaxel in a patient with an exceptional response. 
ASCO Breast Cancer Symposium, abst 156, 2015. 
20. Qi W, et al. BRG1 promotes the repair of DNA double-strand breaks by facilitating 
the replacement of RPA with RAD51. J Cell Science 128:317-30, 2015.  
21. Craig DW, et al. Genome and transcriptome sequencing in prospective metastatic 
triple-negative breast cancer uncovers therapeutic vulnerabilities. Mol Cancer Ther 
12(1):104, 2013. 
22. Juvekar A, et al. Combining a PI3K inhibitor with a PARP inhibitor provides an 
effective therapy for BRCA1-related breast cancer. Cancer Discov 2(11):1048, 2012. 
23. Laplante M, Sabatini DM. mTOR Signaling. Cold Spring Harb Perspect Biol 
2012;4(2). 
24. Laplante M, Sabatini, DM. mTOR Signaling in Growth Control and Disease. Cell 
2012;149(2):274-93. 
25. Sabatini DM. mTOR and cancer. insights into a complex relationship. Nature 
Reviews. Cancer 2006;6(9):729-34. 
26. Benjamin D, Colombi M, Moroni C, Hall MN. Rapamycin passes the torch. a new 
generation of mTOR inhibitors. Nature Reviews. Drug Discovery 2011;10(11):868-
80. 
27. Vilar E, Perez-Garcia J, Tabernero J. Pushing the envelope in the mTOR pathway. 
the second generation of inhibitors. Molecular Cancer Therapeutics 2011;10(3):395-
403. 
28. Thoreen CC, Kang SA, Chang JW, Liu Q, Zhang J, Gao Y, et al. An ATP-
competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant 
functions of mTORC1. Journal of Biological Chemistry 2009;284(12):8023-32. 
MLN0128 Clinical Study Protocol C31004 Amendment 01, EudraCT: 2014-005394-
37 Confidential 97 
29. Chresta CM, Davies BR, Hickson I, Harding T, Cosulich S, Critchlow SE, et al. 
AZD8055 is a potent, selective, and orally bioavailable ATP-competitive 
mammalian target of rapamycin kinase inhibitor with in vitro and in vivo antitumor 
activity. Cancer Research 2010;70(1):288-98. 


 
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30. Rodrik-Outmezguine VS, Chandarlapaty S, Pagano NC, Poulikakos PI, Scaltriti M, 
Moskatel E, et al. mTOR kinase inhibition causes feedback-dependent biphasic 
regulation of AKT signaling. Cancer Discov 2011;1(3):248-59. 
31. Hassan B, Akcakanat A, Takafumi S, Evans K, Adkins F, Meric-Bernstam F. 
Inhibitor MLN0128 Has Antitumor Efficacy In Cell Lines With Intrinsic And 
Acquired Rapamycin-Resistance. Academic Surgical Congress 2013(Abstract 
ASC20130420). 
32. Mondesire WH, Jian W, Zhang H, Ensor J, Hung MC, Mills GB, et al. Targeting 
mammalian target of rapamycin synergistically enhances chemotherapy-induced 
cytotoxicity in breast cancer cells. Clinical Cancer Research 2004;10(20):7031-42. 
33. O'Reilly KE, Rojo F, She QB, Solit D, Mills GB, Smith D, et al. mTOR Inhibition 
Induces Upstream Receptor Tyrosine Kinase Signaling and Activates Akt. Cancer 
Res 2006;66(3):1500-8. 
34. Tabernero J, Rojo F, Calvo E, Burris H, Judson I, Hazell K, et al. Dose- and 
scheduledependent inhibition of the mammalian target of rapamycin pathway with 
everolimus. a phase I tumor pharmacodynamic study in patients with advanced solid 
tumors. J Clin Oncol 2008;26(10):1603-10. 
35. Jessen K, et al. INK128 Is a Potent and Selective TORC1/2 Inhibitor With Broad 
Oral Antitumor Activity. Mol. Cancer Therapy 2009;8(12):Abstract B148. 
36. Kessler L, Wang S, Xin G, Kucharski J, Staunton J, Lan L, et al. INK128, an orally 
active TORC1/2 kinase inhibitor, shows broad antitumor activity and enhances 
efficacy of cytotoxic as well as targeted agents. Cancer Research 2010;70(8; 
Supplement 1 Abstract 4496). 
37. De P, Sun Y, Wu H, Rommel C, Yi L, Dey N, et al. Pre-clinical potency of INK128, 
a highly potent TORC1/2 kinase inhibitor in the HER2 amplified breast cancer 
model. Cancer Research 2012;72(Abstract 2240). 
38. MLN0228 Investigator's Brochure, June 2015. 
39. Yuan TL, Cantley LC. PI3K pathway alterations in cancer. variations on a theme. 
Oncogene 2008;27(41):5497-510. 
40. Stemke-Hale K, Gonzalez-Angulo AM, Lluch A, Neve RM, Kuo WL, Davies M, et 
al. An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT 
mutations in breast cancer. Cancer Research 2008;68(15):6084-91. 
41. Ollikainen M, Gylling A, Puputti M, Nupponen NN, Abdel-Rahman WM, Butzow 
R, et al. Patterns of PIK3CA alterations in familial colorectal and endometrial 
carcinoma. International Journal of Cancer 2007;121(4):915-20. 
42. Spoerke JM, O'Brien C, Huw L, Koeppen H, Fridlyand J, Brachmann RK, et al. 
Phosphoinositide 3-kinase (PI3K) pathway alterations are associated with histologic 
subtypes and are predictive of sensitivity to PI3K inhibitors in lung cancer 
preclinical models. Clinical Cancer Research 2012;18(24):6771-83. 
43. MLN-128 in Combination with MLN1117 (PIKTOR) Investigator's Brochure, July 
2015.  


 
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44. Voss M, Gordon MS, Mita M, Rini B, Makker V, Macarulla T, et al. Phase I study of 
investigational oral mTORC1/2 inhibitor TAK-228 (formerly MLN0128): expansion 
phase in patients with renal, endometrial, or bladder cancer. ESMO poster Sept 2015. 
45. Ghobrial IM, Siegel DS, Vij R, Berdeja JG, Richardson PG, Neuwirth R, Patel CG, 
Zohren F, Wolf JL. Am J Hematol. 2016 Jun;91(4):400-5. TAK-228 (formerly 
MLN0128), an investigational oral dual TORC1/2 inhibitor: A phase I dose 
escalation study in patients with relapsed or refractory multiple myeloma, non-
Hodgkin lymphoma, or Waldenström's macroglobulinemia. 
46. MLN1117 Investigator's Brochure, September 2015. 
 
 


 
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17.    APPENDICES 
Appendix I: Eastern Cooperative Oncology Group (ECOG) Scale for 
Performance Status 
Grade 
Description 
0 
Normal activity.  Fully active, able to carry on all predisease performance without 
restriction 
1 
Symptoms but ambulatory.  Restricted in physically strenuous activity, but 
ambulatory and able to carry out work of a light or sedentary nature (e.g., light 
housework, office work) 
2 
In bed < 50% of the time.  Ambulatory and capable of all self-care, but unable to 
carry out any work activities.  Up and about more than 50% of waking hours. 
3 
In bed > 50% of the time.  Capable of only limited self-care, confined to bed or chair 
more than 50% of waking hours. 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  Totally 
confined to bed or chair 
5 
Dead 
Source:  Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET et al. Toxicity and 
response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982; 5 (6):649-55. 
 
 


 
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Appendix II: Cockcroft-Gault Equation 
For men: 
Creatinine Clearance = 
 (140-age [years])weight [kg] 
72(serum creatinine [mg/dL]) 
OR 
Creatinine Clearance = 
 (140-age [years])weight [kg] 
0.81(serum creatinine [µmol/L]) 
 
For women: 
Creatinine Clearance = 
0.85 (140-age [years])weight [kg] 
72(serum creatinine [mg/dL]) 
OR 
Creatinine Clearance = 
0.85 (140-age [years])weight [kg] 
0.81(serum creatinine [µmol/L]) 
Source: Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 
1976;16(1):31-41. 
. 
 


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


 
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Appendix IV: List of Relevant Cytochrome P450 Inhibitors and Inducers 
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 
 
Source:  fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ 
ucm093664.htm.   
Note that these lists are not exhaustive.   
(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. 
 
 


 
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Appendix V: NCI Common Terminology Criteria for Adverse Events 
(CTCAE), Version 4.0 
 
Publish Date: May 28, 2009 
 
COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS (CTCAE)  
Version 4.0 
 
As of May 28, 2009 (v4.03: June 14, 2010), NCI has edited version 4.0 of the Common 
Terminology Criteria for Adverse Events. These may be obtained at the following web link 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf. 
 
DO NOT USE CTC VERSION 3.0 TO GRADE TOXICITIES IN THIS STUDY! 
 
 
 


 
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Appendix VI: Schedule of Assessments 
Assessment 
 
Prestudy 
 
As per 11.5.1 
During Treatment  
prior to each cycle, unless otherwise specified  
As per 11.5.3 
End of 
Treatment  
up to 30±2 
days following 
As per 11.5.4 
Follow-up  
every 3 months for 1 year 
from the date of last 
treatment 
As per 11.5.5 
PIKTOR 
Chemo,  
Cycles 1-2 
Chemo,  
Cycles 3-6 
(research data 
only) 
Informed consent 
 
 
 
 
 
 
Signed patient authorization (HIPAA) 
 
 
 
 
 
 
Inclusion/exclusion criteria 
 
 
 
 
 
 
Complete medical history 
Within 3 weeks prior 
to registration (PTR) 
 
 
 
 
 
Complete physical examination (including 
vital signs, height, and body weight) 
Within 3 weeks PTR 
 
 
 
 
 
Brief medical history 
 
 
 
 
 
 
Brief physical exam (vitals, weight) 
 
 
 
 
 
 
Assessment of ECOG PS 
Within 3 weeks PTR 
 
 
 
 
 
Assessment of conmeds  
Within 4 weeks PTR 
 
 
 
 
 
CBC with differential and platelet count 
Within 4 weeks PTR 
1 
 
 
 
 
Complete metabolic profile (CMP) 
Within 4 weeks PTR 
2 
 
 
 
 
Coagulation (PT/INR, aPTT) 
Within 3 weeks PTR 
 
 
 
 
 
Fasting lipid profile (total cholesterol, 
HDL-C,LDL-C, triglycerides) 
Within 3 weeks PTR 
 
 
 
 
 
HbA1c 
Within 3 weeks PTR 
3 
 
 
 
 
In-clinic fasting serum glucose 
Within 3 weeks PTR 
4 
 
 
 
 
In-home daily fasting glucose monitoring 
 
5 
 
 
 
 
Serum or urine pregnancy test 
Within 7 days PTR 
 
 
 
 
 
Urinalysis 
Within 4 weeks PTR 
6 
 
 
 
 
EKG 
Within 4 weeks PTR 
As clinically 
indicated 
As clinically 
indicated 
 
 
 
Pulmonary function test (if clinically 
indicated) 
Within 4 weeks PTR 
 
 
 
 
 
Clinical assessment of disease 
Within 3 weeks PTR 
 
 
 
 
 


 
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Assessment 
 
Prestudy 
 
As per 11.5.1 
During Treatment  
prior to each cycle, unless otherwise specified  
As per 11.5.3 
End of 
Treatment  
up to 30±2 
days following 
As per 11.5.4 
Follow-up  
every 3 months for 1 year 
from the date of last 
treatment 
As per 11.5.5 
PIKTOR 
Chemo,  
Cycles 1-2 
Chemo,  
Cycles 3-6 
(research data 
only) 
Radiological assessment of disease  
Within 4-6 weeks 
PTR 
As clinically 
indicated 
As clinically 
indicated 
 
 
As clinically indicated 
Assessment of other lesions 
Within 4 weeks PTR 
To confirm CR 
 
 
 
 
Research biopsies 
Prior to the first day 
of treatment 
At the time of 
PD on PIKTOR, 
prior to nab 
pac/cis 
 
 
 
 
Whole blood (40 mL) 
 
7 
 
 
 
 
Patient diary: glucometer 
 
 
 
 
 
 
Patient diary: PIKTOR dosing 
 
 
 
 
 
 
Toxicity/AE 
 
 
 
 
 
For 30 days following last 
dose 
Survival, relapse or PD, additional therapy 
 
 
 
 
 
 
1 A CBC with differential and platelet count every 14 days for the first Cycle of PIKTOR, Day 1 of PIKTOR cycles thereafter. 
2 A CMP every 14 days for the first Cycle of PIKTOR, Day 1 of PIKTOR cycles thereafter. 
3 HbA1c must be obtained Cycle 1 Day 1, Cycle 3 Day 1 and every 3 PIKTOR cycles thereafter. 
4 Fasting serum glucose will be measured in the clinic. Patients are required to fast overnight (nothing except water and/or medications after midnight or for a minimum of 8 hrs). The sample should be taken 
approximately 2 hrs after study drug administration with the patient continuing to fast until the blood sample is taken. In-home glucose monitoring is not required on days when fasting glucose is measured in 
the clinic. See Section 11.9.1. 
5 Patients will be given a glucometer to monitor fasting glucose levels at home collected daily predose on dosing days, at approximately the same time each day, and will be instructed to notify the PI anytime 
the fasting glucose is abnormal (≥150 mg/dL). 
6 Urinalysis must be obtained prior to Day 1 and Day 15 for Cycle 1, and on Day 1 every subsequent cycle.  
7 Whole blood collection (40 mL) for germline exome sequencing studies at the time of disease progression (or off treatment) on PIKTOR. 
 
 


 
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Appendix VII: Research Biopsies 
Tissue Collection Guidelines for Snap Freezing Tissue for Storage 
 
Tissue will be snap frozen according to the Baylor Biobank Project Management Core (BBPMC) 
protocol. Briefly, immediately after biopsy, tissue will be placed in a screw-capped cryovial, and 
submerged in liquid nitrogen for rapid freezing and preservation of tissue. Tissue will then be 
stored in -80⁰C freezer until further use. 
 
 


 
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Tissue Collection Guidelines for TGen Sequencing Testing 
The purpose of this Standard Operating Procedure (SOP) is to outline the process for snap freezing 
tissue for processing and storage at TGen. Tissue samples will be collected from participants who 
have been properly consented and who have agreed to participate in the research study. Tumor 
tissues are only suitable for molecular studies if frozen in a timely and appropriate manner. The 
purpose of this document is to outline standardized procedures for collection sites to follow for 
snap freezing tissue. 
I. 
SAFETY 
A. Wear personal protective equipment (PPE), such as lab coats and gloves when handling 
liquid nitrogen. 
B. Liquid nitrogen is extremely cold and can cause ‘burns’. Wear gloves that are specially 
made to withstand liquid nitrogen, as well as eye protection and a lab coat to protect skin 
from splashes and spills.  
II. MATERIALS & EQUIPMENT 
1. Container with dry ice (for transport of frozen tissue) 
2. Clean forceps  
3. Liquid nitrogen 
4. Pre-labeled cryovials 
5. Dry shipper 
6. FedEx Airway Bill 
7. Biohazardous bag for shipping 
8. Dry Ice 
9. Personal protective equipment (PPE) to include gloves, lab coat.  
10. TGen Specimen Submission Form 
 
III. PROCEDURES 
This procedure is intended to ensure that tissue samples collected from consented participants 
will be frozen in a safe and efficient manner while eliminating the risks of contamination and 
loss of molecular integrity. To facilitate the use of molecular techniques, tissue that has been 
adequately frozen is vital to obtaining products with high integrity and quality. 
For each biopsy, we will collect two to four, 1-2 centimeter 18-gauge core needle specimens 
from safely accessible tumor. Depending on availability, either two or three cores will be placed 
in externally-threaded cryovials and immediately flash frozen in liquid nitrogen and stored at -
80oC until shipping on dry ice to TGen. An additional tissue core will be formalin-fixed and 
paraffin-embedded.     
A. Tissue Priority 
In cases where there is insufficient accessible tumor for collection of four core needle 
biopsies, sample processing will be prioritized as follows: 
1. Flash frozen core for DNA/RNA analysis  
2. FFPE core for histopathology 
3. Flash frozen cores for biobanking and additional analyses 
 


 
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B. Snap freezing of Tumor Tissue 
1. Treat all tissue as potentially infectious. 
2. Freezing is performed by research study staff as designated by the collection site 
principal investigator. 
3. Have materials and equipment ready for tissue processing prior to surgery. Have 
pre-labeled cryovials ready. 
4. Fresh tumor tissue should be frozen as soon as possible. Optimally, tissue should be 
frozen within 30 minutes from biopsy. 
5. Do not freeze the tissue directly on ice. 
6. Ensure that the biopsied tissue never desiccates or is contaminated by surrounding 
tissue or other samples. Use clean forceps between samples to avoid cross 
contamination. Do not place the sample in contact with formalin at any point in the 
process. Do not add serum to the sample. 
7. With clean forceps, place the specimen to be frozen into an empty screw 
capped cryovial. 
8. Close the cryovial. 
9. Submerge the cryovial with the specimen into liquid nitrogen. The specimen should 
freeze within 30-60 seconds.  
10. Once snap frozen, samples should be packaged with dry ice and immediately 
shipped to the TGen. 
11. If samples cannot be immediately shipped, samples should be placed on dry ice to 
be carried to the freezer or liquid nitrogen storage facility for storage until shipping. 
12. Complete the TGen Specimen Submission and Requisition Form.  Place a patient 
barcode label on the submission form.  The barcode on the Specimen Submission 
and Requisition Form should match the barcode on the informed consent 
document and the tissue collection cryovials. 
a) Send the original form with the specimen.   
b) Keep a copy of the requisition in the patient’s study binder if applicable. 
 
C. Fresh Frozen Tissue shipment to TGen 
NOTE: Ship Monday through Thursday only unless prior notification is made is made 
with TGen.  Do not ship the day before a U.S. Holiday. 
1. Verify the barcode label matches the barcode number of the Specimen 
Submission and Requisition form. 
2. Place cryovial containing frozen specimen in biohazard bag. 
3. Place 2-3 inches of dry ice in the bottom of a Styrofoam cooler.  Place biohazard 
bag in the center of the cooler on top of the dry ice, and then fill the cooler the 
rest of the way with dry ice (preferably pelleted). Place a single paper-towel or 


 
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piece of paper across top of ice, then put lid on the cooler and tape the lid 
tightly to the cooler, sealing all the way around the lid.  
4. Place the cooler in the cardboard box, placing all paperwork associated with the 
case on top of the cooler, and tape shut. 
5. The outermost container must be marked with the words Exempt Human 
Specimen (use labels or write by hand when necessary).  
6. The U.S. DOT does not require these labels; however, IATA does require these 
labels. Therefore, include these labels on all packages in this category to 
streamline processes. Do not put the universal biohazard symbol on the outside 
of an exempt package as this may cause confusion regarding classification. 
7. The outermost container must be labeled with a hazard class 9 label, UN1845, 
and net weight of dry ice in kilograms. The label should be affixed to a vertical 
side of the box (not the top or bottom) and orientated as shown in the picture in 
Appendix V. The maximum allowable net quantity of dry ice allowed per package 
is 200kg. 
8. Verify the following on the FedEx air bill: 
a) Standard Overnight Shipping 
b) The Airbill must include the statement “Dry ice, 9, UN1845, 
number of packages X net weight in kilograms”. FedEx has a 
check box on their Airbill to satisfy their requirement.  
9. Call Courier Service to pick up specimens  
10. Ship frozen tissue to: 
TGen 
Collaborative Sequencing Center 
c/o L Cuyugan 
445 North 5th St. 
Phoenix, AZ  85004 
602-343-8776 
602-343-8545 (fax) 


 
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Watertight 
Primary 
Absorbent 
Pouch 
Watertight 
secondary pack 
-  
i
l
k b
Pressure tested 
envelope 
Place pressure tested 
envelope inside outer 
thermal box and add dry 
ice around samples. 
Shipment Packing Instructions 
for Frozen Shipments 
As per IATA instructions, an 
itemized list of all contents 
must be included between 
the secondary and outer 
packaging. 


 
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Blood Collection Guidelines for TGen Sequencing Testing 
 
I.  Collections at Clinical Site 
a. Blood: Collect 2 to 3 tubes of whole blood in 10 mL purple-top EDTA hematology 
tubes (processing as soon as possible, <1 hour, according to Appendix I). 
 
II.  Further Processing 
a. Buffy Coat isolation per BPM Core standard protocol, and store at -80°C as usual. 
 
III. Kit contents 
 
1.  Three barcoded labels for 10mL purple top EDTA hematology tubes 
 
2.  Four to 6 externally threaded cryovials with barcoded labels  
 
3.  Consent form 
 


 
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Blood Processing for Extraction of Constitutional Analytes at TGen 
 
Blood samples will be drawn from patients who have been through the informed consent process 
for participation in the research study. Blood samples will be obtained by personnel qualified to 
draw blood from participants at the collection site. The purpose of this document is to outline 
standardized procedures for Collection Sites to follow for blood collection.   
 
Collection kits containing all relevant clinical data collection forms, system-generated barcodes to 
pre-label tissue and blood collection tubes, shipping manifests, return labels and materials, and 
appropriate transport documentation will be assembled by trained shipping technicians within the 
TGen repository.  The system-generated barcodes will represent global specimen identifiers that 
will be tracked by a biobanking software solution hosted by TGen.  The system allows the 
assignment of multiple, unique identifiers to a single biospecimen, and the system can generate 
and assign a new, unique barcode label for a biospecimen received from a clinical site that may 
arrive with barcode labels specific to their institution.  The system records the new barcode 
identifier along with the clinical site-specific barcode identifier and the global specimen identifier. 
 
Clinical sites will be provided with SOPs detailing the proper packaging and shipping vessels to be 
employed for each sample type to protect them from loss, damage, and temperature variations 
during shipment. These protocols include the use of insulated packing material, refrigerated gel 
packs, frozen gel packs, dry ice pellets, and liquid nitrogen as appropriate. 
 
I. SAFETY 
Always use universal precautions when dealing with any blood samples.  Dispose of all blood 
collection equipment in the appropriate receptacles at the collection site. 
 
II. MATERIALS & EQUIPMENT 
1. Tourniquet 
2. Alcohol Swab 
3. Phlebotomy needle  
4. Gauze 
5. Pre-labeled purple top EDTA blood collection tubes 
6. Adhesive bandage 
 
III. PROCEDURES 
This procedure is intended to ensure that blood samples will be obtained from consented 
participants in a safe and efficient manner while eliminating the risks of contamination. Patient 
identifiers will remain under HIPAA compliance, and clinical information will be kept in accordance 
with each site’s standard practice.  Sample collection kits containing barcoded tubes for shipping 
samples to the appropriate laboratory will be provided to the collection sites. 
 
A. Timing for Blood Collection 
1. Identify the person responsible for processing the blood. 
2. Contact this person before or soon after blood collection to arrange timely 
processing of the sample. 
 
 


 
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B. Blood Collection Procedure – Preparation 
1. Blood collection must be performed by personnel qualified to draw blood. 
2. Prior to blood collection, identify the participant, verify identification, and check 
that informed consent has been obtained. 
3. Ensure that the barcoded labels on the blood collection tube match the barcode on 
the informed consent document. 
4. Assemble proper equipment to draw blood.  
 
C. Blood Collection Procedure - Venipuncture 
1. Apply tourniquet to expose veins. Do not place too tightly. If superficial veins are 
not easily apparent, force blood into the vein by massaging the arm from wrist to 
elbow, tap the site with index and second finger, apply a warm, damp cloth to the 
site or lower extremity to allow veins to fill. 
2. Select appropriate site for venipuncture. Avoid areas with excessive scars or 
hematomas. While hand and wrist veins are acceptable it is optimal to select an 
antecubital vein. 
3. Prepare the participant’s arm using an alcohol prep. Cleanse in a circular fashion, 
beginning at the site and working outward. Allow to air dry. 
4. Anchor the vein and swiftly insert the needle (at a 15-30 degree angle with the 
surface of the arm) into the lumen of the vein. Avoid excessive probing and trauma 
to the site. 
5. Draw blood 20-30 mL into an evacuated purple top EDTA blood collection tube. 
6. When the last tube to be drawn is filling, remove the tourniquet. 
7. Remove the needle from the participant and apply a gauze and adequate pressure 
to the site of venipuncture to avoid hematoma formation. 
8. If needed, apply an adhesive bandage to the venipuncture site. 
9. Dispose of needles and supplies in a safe manner. 
10. Samples should be slowly inverted 8 to 10 times to ensure the mixing of the sample 
and the anti-coagulant liquid inside the tube. 
11. Recheck that the barcode label on the blood collection tube matches the barcode on 
the informed consent document. 
12. Complete the Specimen Submission Form.  Place a patient barcode label on the 
submission form.  The barcode on the Specimen Submission Form should match the 
barcode on the informed consent document and the blood collection tubes. 
a) Send the original form with the specimen.   
b) Keep a copy of the requisition in the patient’s study binder if 
applicable. 
13. Transfer the specimen and form as soon as possible to research laboratory for 
downstream processing (BPM Core). 
 
 
 


 
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Appendix VIII: Patient Diaries for PIKTOR administration 
PIKTOR Diary 
 
 
Patient:  
 
 
 
 
Dates:  
to 
 
 
When you take your study medication, write the date and time taken in each of the corresponding boxes. Put an “X” in the 
appropriate boxes on a day that you did not take PIKTOR (missed day). TAKE YOUR NEXT DOSE AT THE NEXT SCHEDULED TIME. 
 
PIKTOR (TAK-228 plus TAK-117) should be taken on an empty stomach, with 8 ounces (240 mL) of water. You should not eat for 
2 hours before and 1 hour after each dose. You should take your study drug at about the same time each scheduled dosing day, and 
not take more than what is prescribed. The 2 drugs/capsules that make up PIKTOR must be taken together at the same time. You 
must swallow the study drug whole and not chew it or open it before swallowing. Keep out of reach of children and do not give to 
any other person.  
 
On clinic visit days, when fasting serum glucose must be taken 2 hours after study drug, it is OK for you to take your dose at a 
different time than is typical. Please remember to bring the medication bottles and any remaining medication with you to your next 
study visit or as instructed by the study staff. Please also bring this diary. 
 
 
 
 
 


 
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Side Effects 
Day 
Start Time 
Stop Time 
Treatment 
Time Taken 
Result 
Nausea 
 
 
 
 
 
 
Vomiting 
 
 
 
 
 
 
Diarrhea 
 
 
 
 
 
 
Fatigue 
 
 
 
 
 
 
Loss of Appetite 
 
 
 
 
 
 
Rash 
 
 
 
 
 
 
Mouth Sores 
 
 
 
 
 
 
Constipation 
 
 
 
 
 
 
Other (please describe): 
 
___________________ 
 
 
 
 
 
 
Day of the Week:
Date:
 
 
 
  
/  
/  
 
  
/  
/  
 
  
/  
/  
 
Medications taken before 
PIKTOR Dose, if applicable
Name: 
Time: 
Name: 
Time: 
Name: 
Time: 
Amount of PIKTOR taken: 
Dose Time:
 AM 
 PM 
 AM 
 PM 
 AM 
 PM 
TAK-228 
mg
mg 
mg
TAK-117 
mg
mg 
mg


 
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Side Effects 
Day 
Start Time 
Stop Time 
Treatment 
Time Taken 
Result 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Appendix IX: Patient Diaries for glucometer readings 
Glucometer Diary 
Patient:  
 
 
 
 
Dates:  
to 
 
 
When you take your fasting blood glucose (FBG), write the date and time taken in each of the 
corresponding boxes. Take your FBG before you take your study drug on the study drug dosing 
days. Please take your FBG at the same time each day. If any readings are equal to or above 
150 mg/dL, please call the coordinator of your study! On days you visit the clinic, you do not have 
to take your FBG at home; this will be done for you in the clinic. 
Date 
Time 
Glucose mg/dL