Conditions: Advanced Solid Tumor
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 19
Healthy volunteers: no

Brief summary:
This is an open-label, cohort study to determine the feasibility and tolerability of the combination of TAK-228 and TAK-117 given on days 2-4, 9-11, 16-18, and 23-25 with paclitaxel on days 1, 8, and 15 for one 28-day cycle in patients with advanced solid tumors.

Detailed description:
The goal of this study is to determine a tolerated dose of the combination of TAK-228, TAK-117 and paclitaxel. To do this, investigators will estimate the maximum tolerated dose that is defined as the dose level at which less than one-third of patients will experience a dose-limiting toxicity. A traditional dose escalation design will be used, beginning with the lowest dose level and escalating to the maximum allowable dose level as specified in the protocol. Three patients will be treated one at a time at a given dose level. A maximum of 5 dosing levels results in a maximum sample size of n=30 subjects. Adverse events will be defined using the Common Toxicity Criteria v. 4.0. dose-limiting toxicity is defined as:

* Grade 3 or higher nonhematologic toxicity, despite adequate treatment, except for the following:

  * Grade 3 hyperglycemia lasting ≤14 days (all patients should receive optimal antiglycemic treatment, including insulin, as clinically indicated).
  * Grade 3 rash lasting ≤3 days (all patients should receive topical steroid treatment, oral antihistamines, and oral steroids, if necessary).
  * Inadequately treated Grade 3 nausea and/or vomiting and Grade 3 diarrhea (all patients should receive optimal antiemetic and/or antidiarrheal prophylaxis and/or treatment).
* Grade 4 neutropenia lasting \>7 days in the absence of growth factor support.
* Grade 4 neutropenia of any duration accompanied by fever ≥38.5°C and/or systemic infection.
* Any other ≥Grade 4 hematologic toxicity.
* Inability to administer at least 75% of planned doses of TAK-228 within Cycle 1, due to study drug-related toxicity.
* Any clinically significant occurrence that the investigator and sponsor agree would place patients at an undue safety risk.

Patients experiencing any grade 3 or more hematologic toxicity attributed to the treatment will hold all therapy until resolution of the toxicity to grade 2 or less. If toxicity persists, the patients will be removed from the study. Upon resolution of the toxicity, the patient will restart treatment at the original dose at the discretion of the investigators.

One of the following outcomes will determine the treatment of subsequent patients:

* If none of the three patients experiences a dose-limiting toxicity, the next group of patients will be entered in the next higher dose cohort. All patients within a cohort must have completed at least once cycle (28 days) prior to initiation of the next cohort of patients.
* If one of the three patients experiences a dose-limiting toxicity, three more patients will be accrued at the current dose level. Subsequently, if only one of the six patients treated at this level experiences a dose-limiting toxicity, the dose will be escalated to the next higher dose in the next group of patients. If two or more of the six patients experiences a dose-limiting toxicity, the maximum tolerated dose has been exceeded and is defined as the previous dose at which no more than 1/3 experienced a dose-limiting toxicity.
* If at least two of the three experience a dose-limiting toxicity, the maximum tolerated dose has been exceeded and is defined as the previous dose at which no more than 1/3 experienced a dose-limiting toxicity.

If the lowest allowable dose level exceeds the maximum tolerated dose, the study will be terminated and the combination will not be deemed safe for use in this population. Additionally, the highest dose level will not be exceeded, even if no dose-limiting toxicities are experienced at that dose.

The adverse events overall and by individual adverse events categories will be summarized. Serious adverse events will be summarized in a similar manner. These summaries will be performed overall and for each dose cohort. Investigators will summarize all events as well as the highest grade for a given subject. Investigators will summarize the number of subjects that exhibit a dose-limiting toxicity at each dose cohort and describe the dose-limiting toxicity for each subject, if applicable.

Arms:
arm 1: Paclitaxel 60mg/m2 Day 1, Day 8, Day 15 TAK-228 2mg Days 2-4, Days 9-11, Days 16-18, Days 23-25 TAK-117 100mg Days 2-4, Days 9-11, Days 16-18, Days 23-25 arm 2: Paclitaxel 60mg/m2 Day 1, Day 8, Day 15 TAK-228 2mg Days 2-4, Days 9-11, Days 16-18, Days 23-25 TAK-117 200mg Days 2-4, Days 9-11, Days 16-18, Days 23-25 arm 3: Paclitaxel 80mg/m2 Day 1, Day 8, Day 15 TAK-228 2mg Days 2-4, Days 9-11, Days 16-18, Days 23-25 TAK-117 200mg Days 2-4, Days 9-11, Days 16-18, Days 23-25 arm 4: Paclitaxel 80mg/m Day 1, Day 8, Day 15 TAK-228 3mg Days 2-4, Days 9-11, Days 16-18, Days 23-25 TAK-117 200mg Days 2-4, Days 9-11, Days 16-18, Days 23-25 arm 5: Paclitaxel 80mg/m2 Day 1, Day 8, Day 15 TAK-228 4mg Days 2-4, Days 9-11, Days 16-18, Days 23-25 TAK-117 200mg Days 2-4, Days 9-11, Days 16-18, Days 23-25

Interventions: intervention 1: paclitaxel intervention 2: TAK-228 intervention 3: TAK-117
Intervention descriptions: intervention 1: Paclitaxel will be diluted prior to infusion in 0.9% Sodium Chloride for Injection, USP; 5% Dextrose Injection, USP; 5% Dextrose and 0.9% Sodium Chloride Injection, USP; or 5% Dextrose in Ringer's Injection to a final concentration of 0.3 to 1.2mg/mL. At ambient temperature (approximately 25°C) and room lighting conditions the solution is physically and chemically stable for up to 27 hours. The diluted product will be prepared and stored in glass, polypropylene, or polyolefin containers; DEHP-containing (polyvinyl chloride (PCV)) containers should not be used. Paclitaxel will be administered using a vented Paclitaxel set with in-line 0.22-micron filter and run over 1 hour. intervention 2: TAK-228 will be provided in 30-ct, 60-cc high density polyethylene (HDPE) bottles with polypropylene, child-resistant caps and induction seal. TAK-228 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. intervention 3: TAK-117 will be provided in 30-ct, 60-cc high density polyethylene (HDPE) bottles with polypropylene, child-resistant caps and induction seal. 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.

Protocol document:
Prot_SAP_000.pdf: 
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CLINICAL STUDY PROTOCOL 
 
Protocol #X31025 
A Phase 1 Evaluation of the Safety and Tolerability of TAK-228 in Combination with 
TAK-117 and Paclitaxel in Advanced Solid Tumors 
 
 
 
 
 
 
 
Indication: 
Advanced solid tumors 
Phase: 
1 
 
 
 
 
Protocol History 
Original                                                 March 6, 2017 
      Amendment 1                                       March 26, 2018 
   Amendment 2 
May 1, 2019 
   Amendment 3 
    January 24, 2020 
 
 
 
 
Investigator and Study Center:  
Casey Williams, Pharm.D., BCOP 
Avera Cancer Institute 
1000 East 23rd Street 
Sioux Falls, SD 57105 
(605) 322-3588 
 
 
 
This is an investigator-initiated study. The principal investigator Dr. Casey Williams, (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: A Phase 1 Evaluation of the Safety and Tolerability of TAK-228 in Combination with 
TAK-117 and Paclitaxel in Advanced Solid Tumors 
Phase: 1 
Number of Patients: 2-30 
Study Objectives 
Primary 
• 
To determine the maximum tolerated dose of the combination of TAK-228, TAK-117 and 
paclitaxel for the treatment of patients with advanced solid tumors 
Secondary 
• To determine the objective response rate (according to RECIST 1.1 response criteria) 
Tertiary/Exploratory 
• To describe symptom occurrence and severity and Health Related Quality of Life (HRQOL) 
as measured by the TRSC and HRQOL-LASA respectively 
 
• To assess whether patients with specific alterations respond more favorably to the combination 
Overview of Study Design: 
Phase 1 trial. 3 + 3 design to determine the safety and tolerability of the combination of TAK-
228, TAK-117 and paclitaxel in patients with advanced solid tumors. The maximum tolerable dose 
(MTD) will be assessed, which is the dose level at which less than one-third of patients will experience 
a dose limiting toxicity. 


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Study Population: The study population will consist of patients with advanced solid tumors. 
 
Inclusion Criteria: 
 
• 
Male or female patients 18 years or older 
• 
Patients must have a diagnosis of an advanced solid tumor malignancy and must be refractory 
to or intolerant of existing therapies known to provide a clinical benefit 
• 
Eastern Cooperative Oncology Group (ECOG) performance status and/or other performance 
status of 0-2 
• 
Female patients who: 
o Are postmenopausal for at least 1 year before the screening visit, OR 
o Are surgically sterile, OR 
o If they are of childbearing potential must have a negative pregnancy test and agree 
to practice one effective method of pregnancy prevention contraception and one 
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 [e.g., 
USPI, SmPC, etc.,]) after the last dose of study drug, OR 
o Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the patient. (Periodic abstinence [e.g., calendar, ovulation, sympto- thermal 
and post ovulation methods], withdrawal, spermicides only, and lactational amenorrhea 
are not acceptable methods of contraception. Female and male condoms should not be 
used together.) 
• 
Male patients, even if surgically sterilized (i.e., status post-vasectomy), who: 
o Agree to practice highly effective barrier contraception during the entire study 
treatment period and through 120 days after the last dose of study drug, OR 
o Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the patient. (Periodic abstinence [e.g., calendar, ovulation, sympto- thermal 
and post ovulation methods for the female partner], withdrawal, spermicides only, and 
lactational amenorrhea are not acceptable methods of contraception. Female and male 
condoms should not be used together.) 
o Agree not to donate sperm during the course of this study or within 120 days after 
receiving their last dose of study drug 
• 
Screening clinical laboratory values as specified below: 
o 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 
o 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) 
o Renal: creatinine clearance ≥50 mL/min based either on Cockcroft-Gault estimate or 
based on urine collection (12 or 24 hour) 
o Metabolic: Glycosylated hemoglobin (HbA1c) <7.0%, fasting serum glucose (≤ 130 
mg/dL) and fasting triglycerides ≤300 mg/dL 
• 
Ability to swallow oral medications 
• 
Voluntary written consent must be given before performance of any study related procedure not 
part of standard medical care, with the understanding that the patient may withdraw consent at 
any time without prejudice to future medical care 
• 
Patients who have a history of brain metastasis are eligible for the study provided that all the 
following criteria are met: 


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o Brain metastases which have been treated 
o No evidence of disease progression for ≥3 months before the first dose of study drug 
o No hemorrhage after treatment 
o Off-treatment with dexamethasone for 4 weeks before administration of the first dose of 
TAK-228 
o No ongoing requirement for dexamethasone or anti-epileptic drugs 
 
Exclusion Criteria: 
 
• 
Active central nervous system (CNS) metastasis 
• 
Other clinically significant co-morbidities, in the opinion of the investigators, 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 
• 
Known human immunodeficiency virus infection 
• 
Known hepatitis B surface antigen-positive, or known or suspected active hepatitis C infection. 
• 
Any serious medical or psychiatric illness that could, in the investigator’s opinion, potentially 
interfere with the completion of treatment according to this protocol 
• 
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. 
• 
Breast feeding or pregnant 
• 
Treatment with any investigational products within 30 days before the first dose of study drug 
• 
Previous treatment with PI3K, AKT, dual PI3K/mTOR inhibitors, TORC1/2 inhibitors (prior 
treatment with everolimus is allowed) 
• 
Manifestations of malabsorption due to prior gastrointestinal (GI) surgery, GI disease, or for an 
unknown reason that may alter the absorption of TAK-228. In addition, patients with small 
bowel or jejunal stomata are also excluded. 
 


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• 
History of any of the following within the last 6 months before administration of the first dose 
of the drug: 
o Ischemic myocardial event, including angina requiring therapy and artery 
revascularization procedures 
o Ischemic cerebrovascular event, including transient ischemic attack and artery 
revascularization procedures 
o Requirement for inotropic support (excluding digoxin) or serious (uncontrolled) cardiac 
arrhythmia (including atrial flutter/fibrillation, ventricular fibrillation or ventricular 
tachycardia) 
o Placement of a pacemaker for control of rhythm 
o New York Heart Association (NHYA) Class III or IV heart failure (See Appendix B) 
o Pulmonary embolism 
• 
Significant active cardiovascular or pulmonary disease including: 
o Uncontrolled hypertension (i.e., systolic blood pressure >180 mm Hg, diastolic blood 
pressure >95 mm Hg). Use of anti-hypertensive agents to control hypertension before 
Cycle1 Day 1 is allowed. 
o Pulmonary hypertension 
o Uncontrolled asthma or O2 saturation <90% by arterial blood gas analysis or pulse 
oximetry on room air 
o Significant valvular disease; severe regurgitation or stenosis by imaging independent of 
symptom control with medical intervention, or history of valve replacement 
o Medically significant (symptomatic) bradycardia 
o History of arrhythmia requiring an implantable cardiac defibrillator 
o Baseline prolongation of the rate-corrected QT interval (QTc) (e.g., repeated 
demonstration of QTc interval >480 milliseconds, or history of congenital long QT 
syndrome, or torsades de pointes) 
• 
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 
• 
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 
• 
Patients receiving systemic corticosteroids (either IV or oral steroids, excluding inhalers or 
low-dose hormone replacement therapy – doses of prednisone < 10mg or equivalent are 
allowed) within 1 week before administration of the first dose of study drug 
• 
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 
 
Duration of Study: Patients will complete 3 cycles within their cohort and will be followed until 
disease progression. Patients that have stable disease or better after 3 cycles can continue therapy 
until progression. 
 


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TABLE OF CONTENTS 
 
STUDY OVERVIEW DIAGRAM (optional) ....................................................................... NA 
LIST OF TABLES AND FIGURES (OPTIONAL)  .............................................................. NA 
TABLES ................................................................................................................................. NA 
FIGURES ............................................................................................................................... NA 
LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS  .............................................. 9 
1. INTRODUCTION  .............................................................................................................. 12 
1.1 Disease Under Treatment .............................................................................................. 12 
1.2 Study Drugs ................................................................................................................... 13 
1.2.1 TAK-228 ................................................................................................................ 13 
1.2.2 TAK-117 ................................................................................................................ 13 
2. SUMMARY OF NONCLINICAL EXPERIENCE ............................................................ 14 
2.1 TAK-228........................................................................................................................ 14 
2.1.1 TAK-228 in Combination with Paclitaxel .............................................................. 15 
2.2 Nonclinical Experience with TAK117  .......................................................................... 16 
2.3 TAK-228 in Combination with TAK-117 (PIKTOR) ................................................... 16 
3. SUMMARY OF CLINICAL EXPERIENCE  .................................................................... 17 
3.1 Clinical Experience with TAK-228  ............................................................................... 17 
3.2 Clinical Experience with TAK-117  ............................................................................... 19 
3.3 Clinical Experience with TAK-228 + TAK-117 (PIKTOR; study C32001)  ................ 21 
3.3.1 Pharmacokinetics  .................................................................................................... 21 
3.3.2 Pharmacodynamics  ................................................................................................. 21 
3.3.3 Safety ...................................................................................................................... 22 
3.3.4 Potential Risks  ........................................................................................................ 22 
4. SPECIAL WARNINGS AND PRECAUTIONS  ............................................................... 23 
4.1 Insulin and Glucose Levels ............................................................................................ 23 
4.2 Cardiac Effects  .............................................................................................................. 24 
4.3 Renal Function............................................................................................................... 24 
4.4 Rash ............................................................................................................................... 25 
4.5 Pneumonitis  ................................................................................................................... 25 
4.6 Interactions  ................................................................................................................... 25 
5. RATIONALE FOR THE RP2D FOR PIKTOR (TAK-228 + TAK-117) .......................... 25 
6. STUDY RATIONALE  ....................................................................................................... 26 
Treatment-Related Symptom Checklist ............................................................................... 28 
Potential Biomarkers  ........................................................................................................... 28 
7. STUDY OBJECTIVES  ...................................................................................................... 28 
7.1 Primary Objectives  ........................................................................................................ 28 
7.2 Secondary Objectives  .................................................................................................... 28 
7.3 Tertiary/Exploratory Objectives (if applicable)  ............................................................ 29 
8. STUDY ENDPOINTS ........................................................................................................ 29 
8.1 Primary Endpoints  ......................................................................................................... 29 
8.2 Secondary Endpoints ..................................................................................................... 29 
8.3 Tertiary/Exploratory Endpoints (if applicable)  ............................................................. 29 
9. STUDY DESIGN  ............................................................................................................... 29 
9.1 Overview of Study Design  ............................................................................................ 29 


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9.2 Screening Procedures/Enrollment  ................................................................................. 33 
9.3 Number of Patients  ........................................................................................................ 39 
9.4 Duration of Study  .......................................................................................................... 39 
10. STUDY POPULATION ................................................................................................... 39 
10.1 Inclusion Criteria  ......................................................................................................... 39 
10.2 Exclusion Criteria  ........................................................................................................ 41 
11. STUDY DRUG ................................................................................................................. 43 
11.1 Study Drug Administration  ......................................................................................... 43 
11.2 Definitions of Dose-Limiting Toxicity (Ph1 studies only .................................... 44 
11.3 Dose-Modification Guidelines  .................................................................................... 45 
11.3.1 Criteria for Dose Interruption during a Cycle ...................................................... 46 
11.3.2 Criteria for Discontinuation of Study Drugs  ........................................................ 46 
11.3.3 Recommended Dose Modifications for Paclitaxel Treatment Associated 
Toxicity  ................................................................................................................ 46 
12. EXCLUDED CONCOMITANT MEDICATIONS AND PROCEDURES . .................... 46 
12.1 Permitted Concomitant Medications and Procedures (if applicable)  .......................... 48 
12.2 Precautions and Restrictions  ...................................................................................... 48 
12.3 Management of Clinical Events (if applicable)  ......................................................... 50 
12.3.1 Management of Hyperglycemia  ........................................................................... 52 
12.3.2 Management of Hyperlipidemia  ........................................................................... 53 
12.3.3 Management of Oral Mucositis  ............................................................................ 54 
12.3.4 Management of Rash  ............................................................................................ 55 
12.3.5 Management of Nausea/Vomiting  ........................................................................ 56 
12.3.6 Management of Cardiac Abnormalities ................................................................ 57 
12.3.7 Management of Patients with QTc Prolongation ................................................. 58 
12.3.8 Management of Asthenia, Weakness and Fatigue  ................................................ 59 
12.3.9 Management of Asparte Aminotransferase/Alanine Aminotransferase 
Elevations  ............................................................................................................. 60 
12.3.10 Management of Non-infectious Pneumonitis  ..................................................... 61 
12.4 Description of Investigational Agents  ......................................................................... 61 
12.5 Preparation, Reconstitution, and Dispensing  ............................................................. 62 
12.6 Packaging and Labeling  .............................................................................................. 62 
12.7 Storage, Handling, and Accountability  ....................................................................... 63 
12.8 Study Compliance  ....................................................................................................... 64 
12.9 Termination of Treatment and/or Study Participation  ............................................... 64 
13. Dose Expansion ................................................................................................................. 64 
14. STATISTICAL AND QUANTITATIVE ANALYSES  .................................................. 64 
14.1 Statistical Methods  ...................................................................................................... 64 
15. ADVERSE EVENTS  ....................................................................................................... 65 
15.1 Definitions  ................................................................................................................... 65 
15.1.1 Adverse Event Definition  ..................................................................................... 65 
15.1.2 Adverse Drug Reaction  ....................................................................................... 65 
15.1.3 Serious Adverse Event Definition  ........................................................................ 66 
15.2 Procedures for Reporting Serious Adverse Events  ..................................................... 67 
15.3 Procedures for Reporting Drug Exposure During Pregnancy and Birth Events  ......... 69 
16. ADMINISTRATIVE REQUIREMENTS  ........................................................................ 69 


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16.1 Product Complaints  ..................................................................................................... 69 
17. REFERENCES  ................................................................................................................. 71 
Appendix 1: Eastern Cooperative Oncology Group (ECOG) Scale for Performance  
Status ............................................................................................................... 75 
Appendix 2: Cockcroft-Gault Equation ............................................................................... 76 
Appendix 3: New York Heart Association Classification of Cardiac Disease .................... 77 
Appendix 4: List of Relevant Cytochrome P450 Inhibitors and Inducers ........................... 78 
Appendix 5: Guidelines for TAK-228/117 and Paclitaxel Dose Modification and Delay.. 79 
Appendix 6: Health Related Quality of Life Assessment………………………………….82 
Appendix 7: Therapy Related Symptoms Checklist……………………………………….83 
 


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LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS 
 
Abbreviation 
Term 
AE 
adverse event 
AKT 
Protein kinase B 
ALP/ SGPT 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
API 
active pharmaceutical ingredient 
AST/ SGOT 
aspartate aminotransferase 
BCRP 
breast cancer resistance protein 
BID 
bis in die; twice a day 
CBC 
complete blood count 
CL 
clearance, IV dosing 
CNS 
central nervous system 
CO2 
carbon dioxide 
CR 
complete response 
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 
EOS 
End of Study (visit) 
EOT 
End of Treatment (visit) 
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 


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Abbreviation 
Term 
Hb 
Hemoglobin 
HbA1c 
Glycosylated hemoglobin 
Hct 
Hematocrit 
HDPE 
high-density polyethylene 
hERG 
human ether-à-go-go related gene 
HIV 
human immunodeficiency virus 
Hy’s Law 
Drugs that conform to Hy’s Law have a high potential for severe liver injury 
IB 
Investigator’s Brochure 
IC50 
concentration producing 50% inhibition 
ICF 
informed consent form 
IEC 
independent ethics committee 
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 
LVEF 
Left ventricular ejection fraction 
MedDRA 
Medical Dictionary for Regulatory Activities 
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 
NHL 
non-Hodgkin lymphoma 
NPO 
nothing by mouth 
NYHA 
New York Heart Association 
PD 
progressive disease (disease progression) 
PK 
pharmacokinetic(s) 
PGx 
Pharmacogenomic(s) 


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Abbreviation 
Term 
PO 
per os; by mouth (orally) 
PPI 
Protein 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 
quater in die; 4 times a day 
QOD 
quaque altera die; every other day 
QOL 
quality of life 
QTc 
rate-corrected QT interval (millisecond) of electrocardiograph 
RBC 
red blood cell 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
Recommended phase 2 dose 
SAE 
serious adverse event 
SC 
Subcutaneous 
SD 
stable disease 
TGI 
tumor growth inhibition 
Tmax 
single-dose time to reach maximum (peak) concentration 
TIA 
Transient ischemic attack 
TPN 
Total parental nutrition 
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 
Disease Under Treatment 
The treatment of patients with advanced solid tumors remains unsatisfactory. New combinations 
are needed to improve the outcomes for patients with advanced disease. Thus, successful 
treatment of advanced solid tumors represents a great challenge. The optimal combination, 
sequencing of treatment, and schedule for targeted drugs and chemotherapy has not been 
established. Little is also known regarding the unique molecular characteristics and patterns of 
each individual’s cancer tumor cells. New pathway-driven molecular subtypes are just now 
being elucidated1 and clinical trials with molecularly targeted therapy, for example, in the 
different types of advanced solid tumors are urgently needed using theragnostic information2, 3. 
 
Therapies are being developed to primarily reduce signaling via oncogenic intracellular 
pathways and thereby change transcriptional events that take place within the cancer cell 
nucleus. These novel therapies may potentially benefit cancer patients with all different tumor 
types and at all stages in the cancer process. Previously, factors used to make traditional 
chemotherapy decisions were based on the tissue of origin or histological subtype. But now, in 
the era of precision medicine, therapeutic strategies must be based on the degree of addiction of 
an individual tumor to the pathway being targeted. Identifying the oncogenic drivers of solid 
tumors and having drugs that target these drivers and/or pathways are the keys to the successful 
treatment of cancer in the future. 
 
There were approximately 14.1 million new cases of cancer globally in 2012 (not including skin 
cancer other than melanoma), which resulted in nearly 8.2 million deaths4, and rates are 
increasing as more people live to an old age and as lifestyle changes occur in the developing 
world5. The most common types of cancer in males are lung, prostate, colorectal and stomach, 
and in females, breast, colorectal, lung and cervical4. The addition of skin cancer, other than 
melanoma, would account for around 40% of cases in the total number of new cancers each 
year6, 7. The financial costs of cancer are also staggering and have been estimated at $1.16 trillion 
US dollars per year as of 20104. Although, for the most part, cancer is a disease of old age, 
children are not immune to this disease. In 2012, about 165,000 children under 15 years of age 
were diagnosed with cancer and in children, acute lymphoblastic leukemia and brain tumors are 
most common4. 
 
As an example of solid tumors in women, ovarian cancer is the seventh most common cancer 
(and the 18th most common cancer overall) worldwide. Approximately 239,000 cases were 


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recorded in 2012, accounting for nearly 4% of all new cases of cancer in women (2% overall). 
This cancer is usually fatal, and is the eighth most common cause of cancer death in women 
worldwide (14th overall)8. Cancers of the ovary, fallopian tube, and peritoneal origin exhibit 
similar behaviors and clinical and molecular characteristics. As such, these are often combined 
together and define epithelial ovarian cancer (EOC). About 85–90% of ovarian cancers are 
epithelial carcinomas. 
1.2 
Study Drugs 
1.2.1 
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 two distinct mTOR complexes, TORC1 and TORC2. 
 
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. 
1.2.2 
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. 
 
 


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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 factors9, 10. The mTOR kinase binds with 
other proteins to form two 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)11. 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 apoptosis12, 13. 
 
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 
angiogenesis10. Thus, rapamycin and the rapalogs are only partial inhibitors of TORC110. 
 
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-BP114-16. 
 
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 pathway17, 18. In the presence of rapalogs, the feedback loop 
is abrogated, leading to continued PI3K signaling, TORC2 activation, and subsequent 
phosphorylation of AKT at threonine-308 and serine-473, which markedly enhances the activity 
of AKT10, 13, 19, 20. 


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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 PI4Kα 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 relationship21. 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 TORC218, 21, 22. Dual TORC1/2 inhibition mitigates the 
feedback activation of AKT, which is known to facilitate resistance to TORC1- only inhibitors 
such as rapamycin17. 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). 
2.1.1 
TAK-228 in Combination with Paclitaxel 
Paclitaxel is an anti-mitotic chemotherapeutic agent that interferes with spindle assembly or 
disassembly, thereby increasing mitotic arrest and inducing cancer cell death. Cancer cells, 
however, have the ability to evade mitotic arrest prior to cell death, a mechanism that inevitably 
reduces the efficacy of these anti-mitotic drugs23. The mTORC1 inhibitor rapamycin was 
reported to synergistically enhance the activity of paclitaxel in breast cancer cells24. In an AN3-
CA endometrial tumor xenograft model, TAK-228 in combination with paclitaxel exhibited 
stronger antitumor efficacy compared to paclitaxel alone. TAK-228 has been shown to induce 
G1 cell cycle arrest. Paclitaxel is known to block the progression of cells through G2 into mitosis 
and this G2-M arrest has been proposed to be a prerequisite step for apoptosis induced by 
paclitaxel25. Pretreatment of mTOR inhibitors will arrest cells in G1 phase and may potentially 
antagonize the toxic effect of paclitaxel26. Therefore, TAK-228 should be given after paclitaxel 
administration in order not to interfere with the mechanism of paclitaxel. 
 
 


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2.2 
Nonclinical Experience with TAK117 
Activating somatic missense mutations (e.g., 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%) cancers27-29. 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 NSCLC30. 
 
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 PIK3CAs 
with 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, δ and γ) 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. 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 for either single agent alone. Antitumor activity of 
PIKTOR was assessed in three xenograft models in mice: two breast cancer cell line models, 
HCC70 (triple negative breast cancer, PTEN null) and MDA-MB-361 (HER2 amplified breast 


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cancer with mutated PIK3CA), and one 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. 
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 malignancies31, study INK128-002 in patients 
with multiple myeloma, non-Hodgkin lymphoma and Waldenström macroglobulinemia32 
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×3 days per week (once 
daily for 3 consecutive days followed by a 4-day dosing holiday every week), and QD×5 
days per week (once daily for 5 consecutive days followed by a 2-day dosing holiday every 
week). 
 
A new TAK-228 capsule containing milled active pharmaceutical ingredient (API) was 


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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 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. 


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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 one FIH, dose-finding study in patients with advanced non-hematologic 
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. 
 
TAK-117 is also being investigated in combination with TAK-228 in study C32001as 
described in the following section. 


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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 
CohortsA-C(28-daycycles): 
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/m
2 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 
 
● 
Part 1: dose escalation 
● 
 Part 2: sequential, multistage, adaptive, randomized 
phase 2 expansion at MTD or RP2D 
 
21-day cycles: 
● 
Escalation: MLN1117 (TWTh QW) 
+docetaxel (36 mg/m2 IV M, Wks 1-2) 
● 
Expansion (2 treatment arms): 
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) 
 
Enrolling 
 
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 non-hematologic 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 suggests 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. 
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 pre-dose 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 post-
dose on Cycle 1 Day 24. Based upon the time course of PD data available there appeared to 


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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. 
 
As of the clinical data cutoff for the most recent IB (10 March 2015), the two agents had been 
co-administered in a single open-label, phase 1b study (Study C32001) in patients with 
advanced non-hematologic 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 
TEAEs (three with related AEs). The most frequently reported TEAEs, regardless of causality, 
were nausea, fatigue, diarrhea, vomiting, decreased appetite, increased aspartate 
aminotransferase, stomatitis, ALT, constipation and maculopapular rash. 
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. 
 
 


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Potential overlapping toxicities associated with TAK-228 and TAK-117 include: 
• Dermatologic disorders (pruritus and rash) 
• Gastrointestinal disorders (diarrhea, mucosal inflammation, nausea, stomatitis and 
vomiting) 
• Generalized disorders (anorexia, asthenia, decreased appetite and fatigue) 
• Hematologic disorders (lymphoid and bone marrow depletion) 
• Metabolic 
disorders 
(decreased 
blood 
chloride, 
hypercholesterolemia 
and 
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 sponsor. 
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 (e.g., 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 


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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 9 December 2015, there 
has been one 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). 
 
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 the current IB version). 
 
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 hydronephrosis, any of 
which may have also contributed to dehydration and elevated 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. 


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4.4 
Rash 
Rash observed in clinical studies of TAK-228 tends to be maculopapular and pruritic and has 
ranged from Grade 1–3. 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 
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 × 3QW). The 
MTD for TAK-228 in combination with TAK-117 both given QD × 3 QW was 6 mg TAK-228 
+ 200 mg TAK-117. 
 
 


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Table Dose Limiting Toxicity Observed with TAK-228 + TAK-117 (3 Days Per Week) in 
Study C32001 
 
 
While both combination dose levels were considered safe based on 3+3 rules, the lower dose 
level of 4 mg + 200 mg QD × 3 QW was chosen as the RP2D for milled TAK228 + TAK-117 
for further development. 
6. 
STUDY RATIONALE 
Activation of the PI3K/AKT/mTOR axis (Figure 1; slide 9 in ref. 33) has been implicated as 
playing an important role in the tumorigenesis process in many malignancies34. Activation of 
this pathway through mutation of various genes directly involved in pathway activation or 
through mutation of the suppressor PTEN result in activation of this signaling axis. We 
propose that inhibitors of this pathway in combination with chemotherapy might be efficacious 
in the treatment of advanced solid tumors. 
 
It is hypothesized that blocking both TORC1 and TORC2 complexes is more effective at 
preventing activation of AKT than inhibiting AKT through TORC1 complex inhibition alone33. 
In this regard, TAK-228 is a selective mTOR inhibitor that blocks both TORC1/TORC2-
complex activity. In a clear-cell Renal Cell Carcinoma (ccRCC) xenograft model, TAK-228 was 
more effective than everolimus, a TORC1 complex inhibitor, at inhibiting tumor growth in vivo 
(slide 3 in ref. 33). However, it was also shown that TAK-228 inhibition of TORC1/TORC2 
resulted in a rapid but transient inhibition of AKT phosphorylation and AKT signaling. 
Inhibition of PI3Kα with TAK-117 in combination with TAK-228 led to a more sustained 
inhibition of TORC1 and TORC2 complexes that resulted in a more complete inhibition of 
tumor growth in the ccRCC xenograft model than with TAK-228 alone (slides 8–10 in ref. 33). 


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Figure 1. Sustained inhibition of PI3Ka, TORC1 and TORC2 may be required to be more 
effective than sustained TORC1 and TORC2 inhibition to maximize cancer growth inhibitory 
effects. 
 
The mechanisms by which cells develop resistance to taxanes are not entirely understood. 
Evidence suggests, however, that activation of the PI3K/AKT/mTOR pathway by paclitaxel 
may play a role35-37. Conversely, PI3K inhibitors have been shown to sensitize tumors to the 
effects of paclitaxel37-39. In one study by Hou et al.40, they found that by inhibiting PI3Ks they 
could regulate mitotic progression and prevent mitotic cell death. Therefore, the link between 
taxane resistance and activation of the PI3K/AKT/mTOR signaling pathway suggests that by 
inhibiting this axis in combination with anti-mitotic drugs like paclitaxel may also improve 
treatment outcomes in advanced solid tumors. 
 
Therefore, the rationale for using this combination is that TAK-228 plus TAK-117 will exert 
antitumor effects against advanced solid tumors and enhance the effects of paclitaxel through 
inhibition of cell proliferation and more complete blockade of the PI3K/AKT/mTOR pathway. 
This approach may represent a promising combination to employ as targeted therapy in the 
treatment of advanced solid tumors. We propose to combine TAK-228 with TAK-117 and 
paclitaxel in a phase I trial to determine the safety profile of this combination in advanced solid 
tumors. 


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Exploratory Studies 
Treatment-Related Symptom Checklist 
Symptom occurrence and severity of therapy-related symptoms and health-related quality of life 
(HRQOL) will be described for patients undergoing the treatment regimen described on this 
study. 
 
The Therapy-Related Symptom Checklist (TRSC) is a patient self-report tool that allows for the 
subjective measurement of therapy-related symptom severity41. Patients rate 25 symptoms on 
severity using a five-point scale; other symptoms may be added and rated as well. A higher total 
score on the TRSC indicates greater frequency and severity of symptoms. Prior studies have 
indicated that TRSC scores correlate inversely with the Karnofsky Performance Scale (KPS) and 
have led to improved symptom documentation and management, thereby affecting patients’ 
quality of life42. The TRSC has shown good internal consistency and reliability with a 
Cronbach’s alpha of at least 0.70 in prior studies41. Construct validity is evidenced by previous 
correlations between TRSC scores and clinician-rated Karnofsky scale, as well as scores on a 
quality of life index. 
 
Patient health-related quality of life (HRQOL) will be assessed using the Health-Related Quality 
of Life Linear Analogue Self-Assessment (HRQOL-LASA). The HRQOL-LASAS measures six 
items on a 10-point scale from 0 (as bad as can be) to 10 (as good as can be). These items have 
been validated as measures of global QOL constructs in numerous settings43-47. 
 
Potential Biomarkers 
Most patients who enter this study will have had or will have genomic sequencing performed. 
For patients who have had sequencing completed and for whom results are available, correlations 
with response and presence of the genomic alterations will be assessed. 
7. 
STUDY OBJECTIVES 
7.1 
Primary Objective 
• The primary objective is to determine the maximum tolerated dose of the 
combination of TAK-228, TAK-117 and paclitaxel for the treatment of patients 
with advanced solid tumors 
7.2 
Secondary Objective 
• To determine the objective response rate (according to RECIST 1.1 response 
criteria) 


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7.3 
Tertiary/Exploratory Objectives 
• To assess whether patients with genomic alterations responded more favorably to 
the combination 
• To describe symptom occurrence and severity of therapy-related symptoms and 
Health Related Quality of Life (HRQOL) as measured by the TRSC and HRQOL - 
LASA respectively 
8. 
STUDY ENDPOINTS 
8.1 
Primary Endpoints 
• Safety evaluation 
• Patient tolerance 
8.2 
Secondary Endpoint 
• Objective tumor response (according to RECIST 1.1 response criteria) 
8.3 
Tertiary/Exploratory Endpoints 
• Symptom occurrence and severity of therapy-related symptoms and Health Related 
Quality of Life (HRQOL) as measured by the TRSC and HRQOL-LASA, 
respectively 
• To assess whether patients with genomic alterations respond more favorably to the 
combination 
9. 
STUDY DESIGN 
9.1 
Overview of Study Design 
This is an open-label, cohort study to determine the feasibility and tolerability of the 
combination of TAK-228 and TAK-117 given on days 2-4, 9-11, 16-18, and 23-25 with 
paclitaxel on days 1, 8, and 15 for one 28-day cycle in patients with advanced solid tumors. 
 
In Amendment 3, only cohort 4 will be used and no DLT criteria will be utilized. After enrolling 
3 patients in cohort 5, there was a noticeable increase in toxicity that suggests we have exceeded 
the recommended phase 2 dose (R2PD). No MTD was established, but the dramatic reduction 
in tolerability makes this dose and schedule unsuitable for long-term use. Thus, it was 
determined to proceed with a dose expansion of cohort 4 to further evaluate if this dose and 
schedule would be the eventual RP2D.


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Dosing schema: (3–6 pts. per cohort) 
 
 
 
 
 
 
 
 
 
 
 
 
The goal of this study is to determine a tolerated dose of the combination of TAK-228, 
TAK-117 and paclitaxel. To do this, we will estimate the maximum tolerated dose (MTD) that 
is defined as the dose level at which less than one-third of patients will experience a dose-limiting 
toxicity (DLT). A traditional dose escalation design will be used, beginning with the lowest 
dose level and escalating to the maximum allowable dose level as specified in the protocol. 
Three patients will be treated one at a time at a given dose level. A maximum of 5 dosing 
levels results in a maximum sample size of n=30 subjects. Adverse events will be defined using 
the Common Toxicity Criteria v. 4.0. 
 
Cohort 1 
Cycle 1 
Study Day 
1 
2-4 
8 
9-11 
15 
16-18 
23-25 
Paclitaxel 60mg/m2 
X 
 
X 
 
X 
 
 
TAK-228 2mg 
 
X 
 
X 
 
X 
X 
TAK-117 100mg 
 
X 
 
X 
 
X 
X 
 
Cohort 2 
Cycle 1 
Study Day 
1 
2-4 
8 
9-11 
15 
16-18 
23-25 
Paclitaxel 60mg/m2 
X 
 
X 
 
X 
 
 
TAK-228 2mg 
 
X 
 
X 
 
X 
X 
TAK-117 200mg 
 
X 
 
X 
 
X 
X 


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Cohort 3  
Cycle 1 
Study Day 
1 
2-4 
8 
9-11 
15 
16-18 
23-25 
Paclitaxel 80mg/m2 
X 
 
X 
 
X 
 
 
TAK-228 2mg 
 
X 
 
X 
 
X 
X 
TAK-117 200mg 
 
X 
 
X 
 
X 
X 
 
Cohort 4 
Cycle 1 
Study Day 
1 
2-4 
8 
9-11 
15 
16-18 
23-25 
Paclitaxel 80mg/m2 
X 
 
X 
 
X 
 
 
TAK-228 3mg 
 
X 
 
X 
 
X 
X 
TAK-117 200mg 
 
X 
 
X 
 
X 
X 
 
Cohort 5 
Cycle 1 
Study Day 
1 
2-4 
8 
9-11 
15 
16-18 
23-25 
Paclitaxel 80mg/m2 
X 
 
X 
 
X 
 
 
TAK-228 4mg 
 
X 
 
X 
 
X 
X 
TAK-117 200mg 
 
X 
 
X 
 
X 
X 
 
DLT is defined as: 
• Any death not clearly due to underlying disease or extraneous causes 
• Hy's Law 
o Subjects with AST or ALT elevations > 3 x ULN and total bilirubin elevation >2 
x ULN without initial findings of cholestasis (elevated serum alkaline 
phosphatase) 
• Grade 3 or higher non-hematologic toxicity, despite adequate treatment, except for the 
following: 
o Grade 3 hyperglycemia lasting ≤14 days (all patients should receive optimal 
antiglycemic treatment, including insulin, as clinically indicated) 
o Grade 3 rash lasting ≤3 days (all patients should receive topical steroid treatment, 
oral antihistamines, and oral steroids, if necessary) 
o Inadequately treated Grade 3 nausea and/or vomiting and Grade 3 diarrhea (all 


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patients should receive optimal antiemetic and/or antidiarrheal prophylaxis and/or 
treatment) 
• Patients experiencing any Grade 3 or more hematologic toxicity attributed to the 
treatment will hold all therapy until resolution of the toxicity to Grade 1 or baseline 
levels. If toxicity persists, the patients will be removed from the study. Upon resolution 
of the toxicity, the patient will restart treatment at the original dose at the discretion of 
the investigators.  No dose adjustments are allowed during the DLT phase of the study. 
• Grade 4 neutropenia lasting >7 days in the absence of growth factor support 
• Grade 4 neutropenia of any duration accompanied by fever ≥38.5°C and/or systemic 
infection 
• Grade 3 thrombocytopenia with bleeding 
• Grade 4 thrombocytopenia > 7 days 
• Any other ≥Grade 4 hematologic toxicity 
• Inability to administer at least 75% of planned doses of TAK-228 within Cycle 1, due 
to study drug-related toxicity 
• Any clinically significant occurrence that the investigator and sponsor agree would 
place patients at an undue safety risk 
 
Patients experiencing any adverse event that requires drug to be held should return to Grade 1 or 
baseline before resuming therapy at the current or a reduced dose.  Rash and hyperglycemia are 
permitted exceptions in which therapy may be resumed at Grade 2 or less. 
 
One of the following outcomes will determine the treatment of subsequent patients: 
• If none of the three patients experiences a DLT, the next group of patients will be entered 
in the next higher dose cohort. All patients within a cohort must have completed at least 
once cycle (28 days) prior to initiation of the next cohort of patients. 
• If one of the three patients experiences a DLT, three more patients will be accrued at the 
current dose level. Subsequently, if only one of the six patients treated at this level 
experiences a DLT, the dose will be escalated to the next higher dose in the next group 
of patients. If two or more of the six patients experiences a DLT, the MTD has been 
exceeded and is defined as the previous dose at which no more than 1/3 experienced a 
DLT. 
• If at least two of the three experience a DLT, the MTD has been exceeded and is defined 
as the previous dose at which no more than 1/3 experienced a DLT 
 
If the lowest allowable dose level exceeds the MTD, the study will be terminated and the 


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combination will not be deemed safe for use in this population. Additionally, the highest 
dose level will not be exceeded, even if no DLTs are experienced at that dose. 
 
The adverse events overall and by individual AE categories will be summarized. Serious adverse 
events will be summarized in a similar manner. These summaries will be performed overall and 
for each dose cohort. We will summarize all events as well as the highest grade for a given 
subject. We will summarize the number of subjects that exhibit a DLT at each dose cohort and 
describe the DLT for each subject, if applicable. 
 
Growth factor support may be utilized at the discretion of the PI, but may not be used 
prophylactically in cycle 1. All other routine supportive care may be used in Amendment 3. 
9.2 
Study Procedures 
Screening Procedures/Enrollment 
All subjects must have signed and dated the informed consent and HIPAA Authorization prior 
to any study specific screening procedures being performed. Pre-enrollment screening test and 
evaluations will be used to determine the eligibility of the patient for study inclusion. All 
screening tests and procedures must be completed within 30 days prior to study registration 
and include the following: 
1) Demography and Medical History including documentation of prior regimen 
2) Physical exam including height and weight 
3) Vital signs including: temperature, BP, pulse, respiration rate 
4) Concomitant medications 
5) Performance Status–-ECOG 
6) CBC with differential and platelet count (CBCD) 
7) Coagulation Panel (PT/INR, aPTT) 
8) Urinalysis (UA) 
9) Comprehensive Metabolic Panel (CMP): ALT/SGPT, AST/SGOT, LDH, phosphorus, 
magnesium, calcium, total protein, alkaline phosphatase, total bilirubin (direct and 
indirect bilirubin if total bili is abnormal), HbA1C, fasting glucose, fasting lipid panel 
(Total cholesterol, HDL-C, LDL-C, triglycerides), creatinine clearance (calculated 
using the Cockcroft formula) or creatinine and albumin 
10) Serum pregnancy test, required only for women of child-bearing potential 
11) Electrocardiogram 
12) Tumor Assessment 


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Baseline 
The following baseline assessments are to be performed within 14 days prior to starting 
recommended treatment. Screening clinical evaluations and laboratory assessments may be used 
as the baseline evaluations if they are done within 14 days prior to starting recommended 
treatment. 
 
The investigator/treating physician will need to ensure that the patient’s baseline evaluations still 
meet eligibility criteria or will report any exclusionary criteria to a Clinical Principal 
Investigator for review prior to starting the patient on the recommended treatment. 
• Physical exam including height and weight 
• Vital signs including: temperature, BP, pulse, respiration rate 
• Concomitant medications 
• TRSC (see Appendix 5) 
• HRQOL-LASA (see Appendix 6) 
• Performance Status-ECOG 
• CBC with differential and platelet count (CBCD) 
• Comprehensive Metabolic Panel (CMP): 
ALT/SGPT, AST/SGOT, Alkaline 
Phosphatase, Total Bilirubin, HbA1C, fasting glucose, lipid panel, Creatinine 
Clearance (calculated using the Cockcroft formula) or Creatinine, and Albumin. All 
additional labs are at the discretion of the treating physician. 
• Baseline Tumor Assessment according to RECIST 
o Scans must be performed within the 30 days prior to starting recommended 
treatment 
• Pregnancy Test – to be performed ≤72 hours prior to the first dose of study drug 
•  
On-Study 
For the purposes of this study the following evaluations will be performed: 
• Physical Exam 
• Vital Signs 
• ECOG performance status 
• CBC with differential 
• Coagulation Panel (PT/INR, aPTT) 
• Urinalysis 
• Fasting lipid profile every 3 cycles 
• HgbA1C every 3 cycles 
• Home glucose monitoring if required, per Table 1 Schedule of Study Assessments 


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• Fasting serum glucose on days patient receives paclitaxel (prior to treatment only) 
• Comprehensive Metabolic Panel to include full electrolyte panel with calcium, 
phosphate, and magnesium, LFTs, kidney function tests, total bilirubin (direct bilirubin 
if total bili is abnormal), total protein  
• ECG 
• Tumor Assessment according to RECIST 1.1 will be performed at the end of the 
third cycle, and then every 12 ± 1 week until study discontinuation or disease 
progression, whichever is later. (See Section 7.2) 
• TRSC and HRQOL-LASA 
• Adverse events will be assessed at every visit. Adverse events will be graded according 
to NCI-CTCAE, version 4. For the purposes of this study only the following adverse 
events will be reported: 
o Any grade ≥3 adverse event 
o Any adverse event resulting in treatment dose reduction or discontinuation 
o Any adverse event considered by the treating investigator/treating physician to 
be medically significant 
o Any serious adverse event 
End of Treatment 
At the time the patient discontinues the recommended treatment for disease progression or any 
other reason the following assessments are to be performed within 30 days of last dose of 
treatment: 
• Physical exam 
• CMP and CBCD (labs as described previously) 
• Urinalysis (UA) 
• Fasting lipid profile 
• Fasting serum glucose 
• Tumor Assessment according to RECIST 1.1 (see Section 7) 
• ECG 
• Coagulation Panel (PT/INR, aPTT) 
• Tumor markers for those patients who had elevated tumor markers on last prior regimen 
• Concomitant medications 
• TRSC 
• HRQOL-LASA 
• Assessment of adverse events ongoing at study discontinuation. Adverse events will be 
graded according to NCI-CTCAE, version 4. For the purposes of this study only the 


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following adverse events will be reported: 
o Any grade ≥3 adverse event 
o Any adverse event resulting in treatment dose reduction or discontinuation 
o Any adverse event considered by the treating investigator/treating physician to be 
medically significant 
o Any serious adverse event 
• Reason for discontinuation is to be documented in patient source documents and 
recorded on CRF 
• Any new primary malignancies must be reported to Takeda if occurring within 3 years 
from study initiation 
Follow-Up 
All patients will be contacted for survival status following study discontinuation at 4, 8, 
12, 18 and 24 months. For those patients without disease progression at the end of therapy, tumor 
assessments will be undertaken every 3 months until either disease progression is observed or 
further anti-cancer treatment is initiated. 
 


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Table 1. Schedule of Study Assessments 
Cycle 1 
Cycle 2 
Cycle 3-8 
Subsequent cycles 
Assessments1 
Screening 
Day -30 to 
Day -1 
C1D1 C1D8 C1D15 C1D22 C2D1 C2D8 C2D15 C2D22
D1 
D15 
D1 
Termination 
Demographics 
and 
Medical 
Hi
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
Exam2
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG PS 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Vitals 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology3 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
 
X 
X 
Chemistry3 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
 
X 
X 
Serum 
pregnancy 
t
t
(if
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Coagulation 
Panel
X 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
ECG5 
X 
 
X 
HbA1c 
X 
X 
 
 
 
 
 
 
 
C3D1
 
C6 and q3 cycles 
 
In 
home 
fasting 
l
 
Daily pre-dose from cycle 1 Day 2 through last dose of study drug (may be decreased to once a week 
after the first 2 cycles, as detailed in Management of Hyperglycemia – section 12.3.1) 
 
Urinalysis 
X 
X 
 
X 
 
X 
 
 
 
X 
 
X 
X 
TRSC 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
X 
HRQOL-LASA 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
X 
AE 
assessment
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Cycle 1 
Cycle 2 
Cycle 3-8 
Subsequent cycles 
Tumor 
Assessment7 
(per RECIST 1.1) 
and/or
tumor
X 
 
 
 
 
 
 
 
 
To be completed 
prior to cycle 4 and 
then every 12 weeks 
 
Every 3 cycles at the discretion of the
investigators 
 
1 With the exception of ECGs, assessments may be done within 24-48 hours of dosing with drug administration. 
2 Symptom directed. 
3 Labs as listed in the protocol (section 9.2.1).  Labs that are drawn on clinic days should be drawn while fasting.  Patients are required to 
fast overnight prior to all chemistry panels and must include a blood glucose. 
4 Pregnancy test will be performed for females that are of childbearing potential, and will need to be performed ≤72 hours prior to the first 
dose of study drug 
5 Single, 12-lead ECG will be collected at screening (within 30 days of first dose), EOT and as clinically indicated while on protocol 
therapy.  
6 Patients will be given a glucometer to monitor fasting glucose levels at home collected daily, pre-dose only on dosing days of the TAK 
228 and TAK 117, at approximately the same time each day and will be instructed to notify the study staff any time the fasting glucose 
is abnormal (≥150mg/dL and <160 mg/dL). In-home glucose monitoring is not required on days when fasting glucose is measured in the 
clinic. For further instruction see Management of Hyperglycemia section (section 12.3.1). 
7 Tumor assessment per RECIST 1.1 will be performed at baseline (within 30 days before entering the study), at the end of the third cycle, 
and then every 12 ±1 week until study discontinuation or disease progression, whichever is later.  


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9.3 
Number of Patients 
Total number of patients to be enrolled, 2–30. A patient is considered enrolled on the first 
day of paclitaxel treatment. 
9.4 
Duration of Study 
Each patient will have a disease evaluation after the completion of three  cycles. Patients with 
a minimum response of stable disease or better, may continue study therapy until disease 
progression. They may then be followed up for a period of 24 months. 
10. STUDY POPULATION 
10.1 
Inclusion Criteria 
Patients must have baseline evaluations performed prior to the first dose of study drug and must 
meet all inclusion and exclusion criteria. The Principal Investigator or his designee must review 
results of all baseline evaluations prior to enrollment of that patient, to assure all inclusion and 
exclusion criteria have been satisfied. In addition, the patient must be thoroughly informed 
about all aspects of the study, including the study visit schedule, required evaluations, and all 
regulatory requirements for informed consent. The written informed consent must be obtained 
from the patient prior to enrollment. The following criteria apply to all patients enrolled onto the 
study unless otherwise specified. 
 
Each patient must meet all of the following inclusion criteria to be enrolled in the study: 
1. Male or female patients 18 years or older 
2. Patients must have a diagnosis of an advanced solid tumor malignancy that is 
refractory to or intolerant of existing therapy(ies) known to provide clinical benefit for 
their condition 
3. Eastern Cooperative Oncology Group (ECOG) performance status and/or other 
performance status of 0-2 
4. 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 must have a negative pregnancy test 
and agree to practice one effective method of pregnancy prevention 
contraception and one additional effective (barrier) method, at the same time, 
from the time of signing the informed consent through 90 days (or longer as 


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mandated by local labeling [e.g., 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 [e.g., calendar, ovulation, 
sympto-thermal and post ovulation methods], withdrawal, spermicides only, 
and lactational amenorrhea are not acceptable methods of contraception. Female 
and male condoms should not be used together.) 
5. Male patients, even if surgically sterilized (i.e., status post-vasectomy), who: 
a. Agree to practice highly effective barrier contraception during the entire 
study treatment period and through 120 days after the last dose of study drug, 
OR 
b. Agree to practice true abstinence, when this is in line with the preferred and 
usual lifestyle of the patient. (Periodic abstinence [e.g., calendar, ovulation, 
sympto-thermal and post ovulation methods for the female partner], withdrawal, 
spermicides only, and lactational amenorrhea are not acceptable methods of 
contraception. Female and male condoms should not be used together.) 
c. Agree not to donate sperm during the course of this study or within 120 
days after receiving their last dose of study drug 
6. Screening clinical laboratory values as specified below: 
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 ≥50 mL/min based either on Cockcroft-Gault 
estimate 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 
7. Ability to swallow oral medications 
8. Voluntary written consent must be given before performance of any study related 
procedure not part of standard medical care, with the understanding that the patient may 
withdraw consent at any time without prejudice to future medical care 
9. Patients who have a history of brain metastasis are eligible for the study provided 


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that all the following criteria are met: 
a. Brain metastases which have been treated 
b. No evidence of disease progression for ≥3 months before the first dose of 
study drug 
c. No hemorrhage after treatment 
d. Off-treatment with dexamethasone for 4 weeks before administration of the 
first dose of TAK-228 
e. No ongoing requirement for dexamethasone or anti-epileptic drugs 
10.2 
Exclusion Criteria 
Patients meeting any of the following exclusion criteria are not to be enrolled in the study: 
1. Active central nervous system (CNS) metastasis 
2. Other clinically significant co-morbidities, in the opinion of the investigators, 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, 
potentially interfere with the completion of treatment according to this protocol 
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 
(prior treatment with everolimus is allowed) 
10. Manifestations of malabsorption due to prior gastrointestinal (GI) surgery, GI disease, 
or for an unknown reason that may alter the absorption of TAK-228. In addition, 
patients with small bowel or jejunal stomata are also excluded. 
11. History of any of the following within the last 6 months before administration of the 


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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 B) 
f. Pulmonary embolism 
12. Significant active cardiovascular or pulmonary disease including: 
a. Uncontrolled hypertension (i.e., systolic blood pressure >180 mm Hg, diastolic 
blood pressure >95 mm Hg). Use of anti-hypertensive agents to control 
hypertension before Cycle1 Day 1 is allowed. 
b. Pulmonary hypertension 
c. Uncontrolled asthma or O2 saturation <90% by arterial blood gas analysis or 
pulse oximetry on room air 
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 
g. Baseline prolongation of the rate-corrected QT interval (QTc) (e.g., repeated 
demonstration of QTc interval >480 milliseconds, or history of congenital 
long QT syndrome, or torsades de pointes) 
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 


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15. Patients receiving systemic corticosteroids (either IV or oral steroids (doses of 
prednisone < 10mg or equivalent are allowed), 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 DRUG 
11.1 
Study Drug Administration 
All protocol-specific criteria for administration of TAK-228 + TAK-117 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. TAK-228 
and TAK-117 must always be taken together in this order, 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 (±24 hours of the QW scheduled dosing 
time, or ± 12 hours of the QD or 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 
will be skipped. If emesis occurs after study medication ingestion, the dose will not be re-
administered, 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. 
 


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Study drug will be administered only to eligible patients under the supervision of the investigator 
or identified sub-investigator(s). 
 
Cycles consist of 28 days for all treatment arms. Paclitaxel will be administered once weekly for 
3 consecutive weeks (on Days 1, 8, and 15 of a 28-day treatment cycle) and TAK-228 and 
TAK-117 will be administered together, 3 days per week (on Days 2–4, 9–11, 16–18, and 23–
25 of a 28-day treatment cycle) in all 5 cohorts. Paclitaxel will be administered intravenously 
per its package insert or Summary of Product Characteristics (SmPC)48, 49. 
11.2 
Definitions of Dose-Limiting Toxicity (DLT) 
Dose limiting toxicities are defined according to the AE profile observed during the first 28 
days of study drug administration in phase 1 or 1b of the study and as described below. All 
AEs should be considered possibly related to the study drug unless such relationship can be 
definitively excluded. It is thought that the RP2D is the cohort 4 dosing and have not seen any 
dose-limiting toxicity in the 6 patients who have received this dose and schedule.  
 
Toxicity will be evaluated according to NCI CTCAE version 4.0. A DLT will be defined as any 
of the following events that are considered by the investigator to be at least possibly related 
to treatment with study drug: 
• Any death not clearly due to underlying disease or extraneous causes 
• Hy's Law 
o Subjects with AST or ALT elevations > 3 x ULN and total bilirubin elevation >2 
x ULN without initial findings of cholestasis (elevated serum alkaline 
phosphatase) 
• Grade 3 or higher non-hematologic toxicity, despite adequate treatment, except for the 
following: 
o Grade 3 hyperglycemia lasting ≤14 days (all patients should receive optimal 
antiglycemic treatment, including insulin, as clinically indicated) 
o Grade 3 rash lasting ≤3 days (all patients should receive topical steroid treatment, 
oral antihistamines, and oral steroids, if necessary) 
o Inadequately treated Grade 3 nausea and/or vomiting and Grade 3 diarrhea (all 
patients should receive optimal antiemetic and/or antidiarrheal prophylaxis 
and/or treatment) 
• Patients experiencing any Grade 3 or more hematologic toxicity attributed to the 
treatment will hold all therapy until resolution of the toxicity to Grade 1 or baseline 


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levels. If toxicity persists, the patients will be removed from the study. Upon resolution 
of the toxicity, the patient will restart treatment at the original dose at the discretion of 
the investigators.  No dose adjustments are allowed during the DLT phase of the study. 
• Grade 4 neutropenia lasting >7 days in the absence of growth factor support 
• Grade 4 neutropenia of any duration accompanied by fever ≥38.5°C and/or systemic 
infection 
• Grade 3 thrombocytopenia with bleeding 
• Grade 4 thrombocytopenia > 7 days 
• Any other ≥Grade 4 hematologic toxicity 
• Inability to administer at least 75% of planned doses of TAK-228 within Cycle 1, due 
to study drug-related toxicity 
• Any clinically significant occurrence that the investigator and sponsor agree would 
place patients at an undue safety risk 
 
Patients who experience an AE that meets the definition of a DLT during or after completing 
Cycle 1 should have their study drug treatment interrupted. If the event resolves to Grade 1 or 
Grade 2 for hyperglycemia or rash or baseline values within 3 weeks of interrupting planned 
therapy, and in the opinion of the investigator the benefits of continuing treatment outweigh the 
risks posed by the toxicity, patients may continue study treatment with TAK-228 dose 
reduction. 
11.3 
Dose-Modification Guidelines for all Cycles 
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 (see tables 
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 and with the sponsor’s approval. 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 


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unless the patient has a Grade 3 or greater TAK-228 and/or TAK-117 related event. 
 
Management of neutropenia and thrombocytopenia may be done at the discretion of the 
investigators. Please see Appendix 5 for guidance. 
 
11.3.1  Criteria for Dose Interruption during a Cycle 
Administration of TAK-228 + TAK-117 should be withheld for treatment-related toxicities that 
are Grade 3 or higher, despite supportive treatment per standard clinical practice. The following 
non-hematologic 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 Dose Reduction Schedule for TAK-228 and TAK-117 
Cohort 
TAK-228 Dose TAK-117 Dose TAK-228 # of Capsules and Strength 
1 
1 mg QD x 3 
100 mg 
One 1 mg capsule 
2 
1 mg QD x 3 
200 mg 
One 1 mg capsule 
3 
1 mg QD x 3 
200 mg 
One 1 mg capsules 
4 
2 mg QD x 3 
200 mg 
Two 1 mg capsules 
5 
3 mg QD x 3 
200 mg 
Two 1 mg capsules 
11.3.2 
Criteria for Discontinuation of Study Drugs 
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, stop 
TAK-228 + TAK-117, discontinue the subject from the study, and complete the EOT visit within 
30 days of the last administration of TAK-228 + TAK-117 whichever is discontinued last. 
11.3.3 
Recommended Dose Modifications for Paclitaxel Treatment Associated 
Toxicity 
Paclitaxel dose modifications may be done at the discretion of the investigators. Please see 


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Appendix 5 for guidance. 
12. 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 (e.g., methotrexate, imatinib, topotecan, lapatinib, rosuvastatin, etc.) and organic 
cation transporter protein 1 or 2 (OCT1 or OCT2) substrates (e.g., 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. 
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, targeted agents, radiation or surgery (subjects can have palliative 
radiation or surgery in the study for pre-existing lesions 
• Systemic corticosteroids (either IV or oral steroids, excluding inhalers), unless 
necessary for treatment of TAK-228 related AE, i.e., rash or other emergent conditions 
that require intervention. Pre-medication for paclitaxel is allowed 
• Anti-epileptic drugs for subjects with treated brain metastasis 
• Concomitant administration of any PPI is not permitted during the study. Patients 


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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. 
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 that apply to the use of CYP3A4, CYP2C19 and CYP2C9 
inhibitors and inducers, histamine H2 receptor antagonists, neutralizing antacids, 
calcium and anti-gas preparations 
12.1 
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. 
 
Neutralizing antacid preparations (acid neutralizers) and calcium supplements are not permitted 
during Cycle 1 on study drug administration days in the phase 1/1b portion of the study, but 
may be taken as needed on non-TAK-228 + TAK-117 administration days. However, for all 
other cycles in the phase 1b portion of the study and throughout the phase 2 portion of the study, 
administration of neutralizing antacids and calcium preparations is permitted except from 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. Alternative 
treatments, if available, should be considered. 
 
Prophylactic use of antiemetic, anti-nausea, and antidiarrheal medications is encouraged and 
may be used before each TAK-228 and TAK-117 dosing as needed throughout the study. 
 
Other medications considered necessary for the safety and well-being of the patient may be 
administered at the discretion of the investigator. 


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12.2 
Precautions and Restrictions 
The use of live vaccines and close contact with those who have received live vaccines 
should be avoided during treatment with study drug. Examples of live vaccines are: intranasal 
influenza, measles, mumps, rubella, oral polio, Bacille Calmette-Guerin (BCG), yellow fever, 
varicella and TY21a typhoid vaccines. 
 
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. 
 
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 [e.g., USPI, SmPC, etc.;]) after the last dose of study 
drug, OR 
o Agree to practice true abstinence, when this is in line with the preferred and 
usual lifestyle of the patient. (Periodic abstinence [e.g., calendar, ovulation, 
sympto- thermal and post ovulation methods], withdrawal, spermicides only 


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and lactational amenorrhea are not acceptable methods of contraception. Female 
and male condoms should not be used together.) 
• Male patients, even if surgically sterilized (i.e., status post vasectomy), 
who: 
o Agree to practice highly effective barrier contraception during the entire study 
treatment period and through 120 days after the last dose of study drug, OR 
o Agree to practice true abstinence, when this is in line with the preferred and 
usual lifestyle of the patient. (Periodic abstinence [e.g., calendar, ovulation, 
sympto- thermal, post ovulation methods for the female partner], withdrawal, 
spermicides only, and lactational amenorrhea are not acceptable methods of 
contraception. Female and male condoms should not be used together.) 
o Agree not to donate sperm during the course of this study or 120 days after 
receiving their last dose of study drug 
12.3 
Management of Clinical Events/Dose Modifications 
12.3.1 
Management of Hyperglycemia 
In normoglycemic patients (no previously diagnosed diabetes mellitus, FBG and HbA1c within 
normal limits at screening), FBG should be checked at the clinic visits, every two weeks during the 
first cycle of treatment then day 1 of each subsequent cycle. In addition, HbA1c will be measured 
every 3 cycles.  
 
In patients with prediabetes (FPG 100-125 mg/dL, 2-h plasma glucose 140-199 mg/dL, HbA1c 5.7-
6.4% at screening), in addition to obtaining fasting serum glucose levels at the clinic visits as 
outlined in the SCHEDULE OF EVENTS, patients randomized to receive TAK-228 will be 
provided with a glucometer and trained in its use to monitor their daily predose fasting blood glucose 
levels at home. The level should be collected daily, predose on dosing days, and at approximately 
the same time each day. Patients will be instructed to notify the study staff of any abnormal 
readings ≥150 mg/dL and <160 mg/dL at the next office visit. Patients will be instructed to notify 
the study staff immediately with any reading > 160 mg/dL for further instructions on the 
management of their hyperglycemia. Hyperglycemia observed during home glucose monitoring 
should be confirmed in the clinic. Investigators will be responsible for reviewing the home glucose 
monitoring logs for hyperglycemia. If no irregularities in the FPG level are observed during a 
minimum of 2 consecutive cycles, then the frequency of in-home FBG testing can be reduced to a 
minimum frequency of once weekly (day 4, 11, 18, and 25) depending on the investigator’s 
judgment and approval. Patients will continue to notify the investigator of FBG levels ≥150 mg/dL, 


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and if blood glucose levels are not well controlled, or if they require 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 and hyperglycemia is managed aggressively as described in Table below.  
For the patients with pre-existing diabetes or patients with a HbA1c >7, self-monitoring should be 
intensified. It is recommended to initiate a treatment with metformin, the first-line drug for 
management of hyperglycemia, when FBG is above 160 mg/dL, when 2-h plasma glucose is above 
200 mg/dl at any time or when HbA1c is above 6.5%. To aggressively manage the hyperglycemia 
per standard clinical practice, the guidelines are provided to aid the investigator in initiating 
antiglycemic therapies. 
 
For the patients with known diabetes mellitus, it is recommended to initiate a treatment 
with metformin, the first-line drug for management of hyperglycemia, when FBG is above 
126 mg/dl (7.0 mmol/l), when plasma glucose is above 200 mg/dl at any time or when HbA1c is 
above 6.5%. 
 
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, have been Grade 1 or 
Grade 2, and have responded quickly to oral metformin. Hyperglycemia has not been dose limiting 
since instituting a standard regimen for early treatment of hyperglycemia. All patients developing 
hyperglycemia on the study should have their glucose closely monitored by study staff. The 
investigator may choose either to continue close monitoring of patients who develop Grade 1 
hyperglycemia (FBG >ULN ≤160 mg/dL) or consider initiating treatment with an oral 
hypoglycemic agent, such as metformin. All patients with ≥ Grade 2 hyperglycemia (FBG 
>160 mg/dL) should be treated aggressively with oral hypoglycemic agents and/or insulin as 
clinically indicated while continuing on TAK-228 treatment. The investigator should consult an 
endocrinologist if needed to aid in optimizing the hyperglycemia treatment plan for the patient. 
 
It is recommended that patients be treated initially with a fast-acting insulin sensitizer, such as 
metformin at 500 mg orally daily, and titrate up to a maximum of 1000 mg orally twice daily as 
needed. Concurrent addition to metformin of dipeptidyl peptidase-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. 
Guidance on study drug dose modification for patients with hyperglycemia is provided in the 


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table below: 
 
Table: 
Management of Hyperglycemia 
Grade 
Description 
Treatment 
Dose Modification 
1 
Fasting 
blood 
glucose: FBG >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 by 1 dose level and resume 
TAK-117 at same dose and 
schedule 
• >2 weeks: discontinue patient 
from the study. 
Prevention/Prophylaxis: 
• 
Follow fasting glucose levels during clinic visits. 
• 
Monitor home glucometer test results. 
• 
Check HbA1c levels every 3 cycles 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. 


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12.3.2 
Management of Hyperlipidemia 
Guidance on study drug dose modification for patients with hyperlipidemia is provided 
below. 
Table: 
Management of Hyperlipidemia 
Grade 
Description 
Treatment 
Dose Modification 
1 
Cholesterol >ULN to 300 mg/dL 
OR 
Triglycerides >150 to 300 mg/dL 
None 
None 
2 
Cholesterol >300 to 400 mg/dL 
OR 
 
Triglycerides >300–500 mg/dL 
Treat hyperlipidemia according 
to standard guidelines. 
Triglycerides ≥500 mg/dL should 
be treated urgently, due to risk 
of pancreatitis. 
Maintain dose, if tolerable. 
 
If toxicity becomes intolerable, 
interrupt TAK-228 and TAK-
117 until recovery to ≤Grade 
1. Re-initiate TAK-228 
+TAK-117 at the same dose 
level 
3 
Cholesterol >400–500 mg/dL 
OR 
Triglycerides >500–1000 mg/dL 
Same as for Grade 2 
Hold TAK-228 and TAK- 117 
until recovery to ≤Grade 1, then 
reinitiate TAK-228 at a dose 
reduced by 1 level and resume 
TAK-117 at same dose and 
schedule 
 
4 
Cholesterol >500 mg/dL 
OR 
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 ofnormal. 
 


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12.3.3 
Management of Oral Mucositis 
Guidance on study dose modification for patients with oral mucositis is provided below. 
Table: 
Management of Oral Mucositis 
Grade 
Description 
Treatment 
Dose Modification 
1 
Asymptomatic or 
mild 
symptoms. 
Nonalcoholic mouthwash, 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 all drugs until recovery to 
≤Grade 1, then restart TAK-
228 at a dose reduced by 1 
level and resume TAK-117 at 
same dose and schedule 
 
4 
Life-threatening 
consequences. 
Same as for Grade 2 
Consider intra-lesional corticosteroids 
Stop all drugs and discontinue 
patient from the study 
Prevention/Prophylaxis: 
• 
Initiation of a nonalcoholic mouth wash, or 0.9% salt water rinses 4–6 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. 
 


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12.3.4 
Management of Rash 
Guidance on study drug dose modification for patients with rash is provided below. 
Table: 
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 
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 by 1 
dose level and resume TAK-117 
at same dose and schedule 
• >3 weeks: stop TAK-228 and 
TAK-117 and discontinue patient 
from the study 
4 
Rash acneiform/ 
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 at the 
discretion of the treating physician and investigators. 
 


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12.3.5 
Management of Nausea/Vomiting 
Guidance for patients with nausea and/or vomiting is provided in the table below. 
Table Management of Nausea/Vomiting 
Grade 
Description 
Treatment 
Dose Modification 
≤2 
Loss of  appetite 
with  or 
without decreased oral intake; 
1–5 episodes of vomiting 
within 24 hours. 
Maximize anti-emetic therapy. 
Consider IV fluid hydration. 
None 
≥3 
Inadequate 
oral 
intake; 
≥6 
episodes 
of 
vomiting 
within 24 hours. 
Maximize anti-emetic therapy. 
Initiate tube feeding, IVF or 
TPN. 
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 ≤ 
Grade 1, then resume treatment 
with the dose of TAK-228  
reduced by 1 level and resume 
TAK-117 at same dose and 
schedule. 
 
Prevention/Prophylaxis: 
Prophylactic use of antiemetic, anti-nausea, and antidiarrheal medications is encouraged and may be used 
before each TAK-228 and TAK-117 dosing as needed throughout the study. 
IV=intravenous, IVF=intravenous fluids, TPN=total parental nutrition. 
 


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12.3.6 
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: 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 
 


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12.3.7 
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 Management of QTc Prolongation 
Grade 
Description 
Treatment 
Dose Modification 
2 
480 msec <QTc 
<501 msec 
Evaluate for other possible causes (e.g., 
electrolyte 
disturbance, 
concomitant 
medication, etc.). 
None; continue TAK-228 and TAK-117 at 
the same dose and schedule. 
≥3 
QTc ≥501 msec 
Evaluate for other possible causes (e.g., 
electrolyte 
disturbance, 
concomitant 
medication); 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 all drugs 
 
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/ 


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12.3.8 
Management of Asthenia, Weakness and Fatigue 
Guidance on dose adjustment for patients with other non-hematologic toxicities is provided 
below. 
Table 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 all drugs until recovery to ≤ 
Grade 1. Reinitiate TAK-228 at 
dose reduced by 1 level and 
resume TAK-117 at same dose 
and schedule. 
 
Patients who develop Grade 4 non-
hematological toxicities (with the 
exception 
of 
isolated 
non- 
clinically significant laboratory 
values) 
should 
permanently 
discontinue 
study 
treatment, 
unless 
they 
derive 
clinical 
benefit, in which case they may 
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12.3.9 
Management of Asparte Aminotransferase/Alanine Aminotransferase 
Elevations 
Guidance on dose adjustment for patients with AST/ALT elevations is provided below. 
Table 
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; >3×ULN with the 
appearance 
of 
worsening 
fatigue, nausea, vomiting, right 
upper 
quadrant 
pain 
or 
tenderness, fever, rash, or 
eosinophilia. 
Closely monitor LFTs at least 
weekly or more frequently as 
indicated. 
Assess patient for other causes of 
transaminitis 
(e.g., 
past 
medical history, concomitant 
medications). 
None 
3 
>5 to 20×ULN; >5×ULN for 
>2 weeks 
Same as for Grade 2. 
Hold paclitaxel, TAK-228 and 
TAK-117 until ≤ Grade 1; 
Restart all drugs at the same 
dose. Permanently discontinue 
study 
treatment 
if 
in 
combination with Grade 2 
total bilirubin elevation when 
alternative causes cannot be 
identified (i.e., Hy’s Law); 
4 
>20×ULN 
Same as for Grade 2. 
Stop paclitaxel, 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 (i.e., 
Hy’s Law). 
Prevention/Prophylaxis: 
Ensure proper screening of patients for study participation. 
LFTs=liver function tests, ULN=upper limit of normal. 


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12.3.10 Management of Non-infectious Pneumonitis 
Guidance for the management of pneumonitis is provided below. 
Table 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 at a 
dose reduced by 1 level 
and resume TAK-117 at 
same dose and schedule. 
 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 
all 
drugs 
until 
symptoms resolve to 
≤Grade 1. 
Consider reinitiating TAK-
228 at a dose reduced by 
1 level and resume TAK-
117 at same dose and 
schedule 
 
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 all drugs. 
12.4 
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: 


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• 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 (TAK-228), MLN1117 (TAK-117), and MLN0128 + MLN1117 (TAK-
228 + TAK-117) IBs for full details. 
12.5 
Preparation, Reconstitution, and Dispensing 
TAK-228 and TAK-117 
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. 
 
Paclitaxel 
Paclitaxel will be diluted prior to infusion in 0.9% Sodium Chloride for Injection, USP; 5% 
Dextrose Injection, USP; 5% Dextrose and 0.9% Sodium Chloride Injection, USP; or 5% 
Dextrose in Ringer’s Injection to a final concentration of 0.3 to 1.2mg/mL. At ambient 
temperature (approximately 25°C /77°F) and room lighting conditions the solution is physically 
and chemically stable for up to 27 hours. 
 
The diluted product will be prepared and stored in glass, polypropylene, or polyolefin containers; 
DEHP-containing (polyvinyl chloride (PCV)) containers should not be used. 
 
Paclitaxel will be administered using a vented Paclitaxel set with in-line 0.22-micron filter and 
run over at least 1 hour. 
 
All patients should be pre-medicated prior to paclitaxel infusion with corticosteroids, 
diphenhydramine, and H2 antagonists, in order to prevent severe hypersensitivity reactions. 
 


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12.6 
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 high density polyethylene (HDPE) bottles with 
polypropylene, child-resistant caps and induction seal. TAK-228 will contain 30 capsules per 
bottle. TAK-117 will contain 14 capsules per bottle. 
 
TAK-228 and TAK-117 are packaged and labeled in accordance with all applicable regulations. 
12.7 
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. 
 
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are stable until the date indicated on the package when stored between 20 to 25°C (68 to 77°F), 
and protected from light. 
 


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12.8 
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 maintain 
records of study drug receipt and dispensing. 
12.9 
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. The investigator also has the right to 
withdraw patients from the study for any of the following reasons: 
• Adverse event 
• Protocol violation 
• Lost to follow-up 
• Progressive disease 
• Study terminated 
• Other 
Patients who are withdrawn from the study will not be replaced. At the time of withdrawal, all 
study procedures outlined for the End of Study visit should be completed. The primary reason 
for patient’s withdrawal from the study should be recorded in the source documents and CRF. 
 
13.  Dose Expansion 
After completion of the DLT phase, the projected phase 2 dose and schedule may be expanded 
to fill any remaining patient slots up to a maximum of 30 patients under amendment 3 of this 
protocol. There will be no restriction on how many patients can be enrolled concomitantly and 
all patients may utilize any applicable supportive therapy during the first cycle, including GCSF. 
Further, all patients will receive modified blood glucose monitoring and be stratisfied based 
upon their history of hyperglycemia and response to therapy. 
14. STATISTICAL AND QUANTITATIVE ANALYSES 
14.1 
Statistical Methods 
The demographic and clinical characteristics of the study patients will be summarized using 
descriptive statistics 
• Primary objective: The maximum tolerable dose (MTD) will be assessed, which is 
the dose level at which < one-third of patients will experience a dose-limiting toxicity 


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(DLT) 
• Secondary objectives: 
1. Adverse events will be defined according to the CTCAE v. 4.03 and will be 
summarized with descriptive statistics 
2. Response rate will be determined according to the RECIST 1.1 response 
criteria. Number and type of responses will be summarized with descriptive 
statistics 
• Exploratory objectives 
1. Response rate and relationship with genomic alterations will be examined by 
using a two-sided Fisher Exact test due to the small sample sizes 
2. TRSC and HRQOL-LASA scores will be summarized with descriptive statistics 
15. ADVERSE EVENTS 
15.1 
Definitions 
15.1.1 
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 
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. 
15.1.2 
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. 


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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. 
15.1.3 
Serious Adverse Event Definition 
Serious AE (SAE) means any untoward medical occurrence that at any dose: 
• Results in death 
• Is life-threatening (refers to an AE in which the patient was at risk of death at the 
time of the event. It does not refer to an event which hypothetically might have 
caused death if it were more severe). 
• Requires inpatient hospitalization or prolongation of an existing hospitalization 
(see clarification in the paragraph below on planned hospitalizations). 
• Results in persistent or significant disability or incapacity. (Disability is defined 
as a substantial disruption of a person’s ability to conduct normal life functions). 
• Is a congenital anomaly/birth defect 
• Is a medically important event. This refers to an AE that may not result in death, be 
immediately life threatening, or require hospitalization, but may be considered serious 
when, based on appropriate medical judgment, may jeopardize the patient, require 
medical or surgical intervention to prevent 1 of the outcomes listed above, or involves 
suspected transmission via a medicinal product of an infectious agent. Examples of 
such medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse; 
any organism, virus, or infectious particle (e.g., prion protein transmitting 
Transmissible Spongiform Encephalopathy), pathogenic or nonpathogenic, is 
considered an infectious agent. 
Clarification should be made between a serious AE (SAE) and an AE that is considered severe 
in intensity (Grade 3 or 4), because the terms serious and severe are NOT synonymous. The 
general term severe is often used to describe the intensity (severity) 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 


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(severe) but may not be considered serious. Seriousness (not intensity) serves as a guide for 
defining regulatory reporting obligations. 
15.2 
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 
TAK-228. Any SAE that occurs at any time after completion of TAK-228 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 period (up to 24 months) 
must be reported. 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 (e.g., surgery was performed earlier or later than 
planned). All SAEs should be monitored until they are resolved or are clearly determined to be 
due to a patient’s stable or chronic condition or intercurrent illness (es). 
 
Since this is an investigator-initiated study, the principal investigator Dr. Casey Williams, also 
referred to as the sponsor-investigator, is responsible for reporting serious adverse events (SAEs) 
to any regulatory agency, data safety board, or IRB. 
 
Fatal and Life Threatening SAEs within 24 hours of the sponsor-investigator’s 
observation or awareness of the event 
 
All other serious (non-fatal/non life threatening) events within 4 calendar days of 
the sponsor-investigator’s observation or awareness of the event 
 
 


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The sponsor-investigator or designee will send all SAE reports to Takeda Pharmacovigilance 
(or designee) within 24 hours but no later than 4 calendar days as per any agreements. 
 
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 
15.3 
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 8.2). The pregnancy must be followed for the final 
pregnancy outcome (i.e., 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 8.2). Every effort should be made 
to follow the pregnancy for the final pregnancy outcome. 
 
Suggested Pregnancy Reporting Form: 
Pregnancy Report Form (a sample will be provided) 
16. ADMINISTRATIVE REQUIREMENTS 
16.1 
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. 
 


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Individuals who identify a potential medication error situation should immediately contact 
Takeda (see below) and report the event. 
 
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 8.2). 
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 


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17. REFERENCES 
1. 
Lopez J, Banerjee S, Kaye SB. New developments in the treatment of ovarian cancer--future 
perspectives. Annals of oncology: official journal of the European Society for Medical Oncology 
/ ESMO. 2013;24 Suppl 10:x69-x76. 
2. 
Despierre E, Yesilyurt BT, Lambrechts S, et al. Epithelial ovarian cancer: rationale for changing 
the one-fits-all standard treatment regimen to subtype-specific treatment. International journal of 
gynecological cancer : official journal of the International Gynecological Cancer Society. 
2014;24:468-477. 
3. 
Pene F, Courtine E, Cariou A, Mira JP. Toward theragnostics. Critical care medicine. 
2009;37:S50-58. 
4. 
Stewart B. World cancer report 2014: International Agency for Research onCancer,WHO Press, 
World Health Organization; 2014. 
5. 
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA: a cancer 
journal for clinicians. 2011;61:69-90. 
6. 
Cakir BO, Adamson P, Cingi C. Epidemiology and economic burden of nonmelanoma skin 
cancer. Facial Plast Surg Clin North Am. 2012;20:419-422. 
7. 
Dubas LE, Ingraffea A. Nonmelanoma skin cancer. Facial Plast Surg Clin North Am. 
2013;21:43-53. 
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18. 
Hassan B, Akcakanat A, Takafumi S, Evans K, Adkins F, Meric-Bernstam F. MTOR Inhibitor 
MLN0128 has Antitumor Efficacy in Cell Lines With Intrinsic and Acquired Rapamycin-
Resistance. Journal of Surgical Research.179:313. 
19. 
O'Reilly KE, Rojo F, She QB, et al. mTOR inhibition induces upstream receptor tyrosine kinase 
signaling and activates Akt. Cancer research. 2006;66:1500-1508. 
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target of rapamycin pathway with everolimus: a phase I tumor pharmacodynamic study in 
patients with advanced solid tumors. Journal of clinical oncology : official journal of the 
American Society of Clinical Oncology. 2008;26:1603-1610. 
21. 
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inhibitor with broad oral antitumor activity. Molecular cancer therapeutics. 2009;8:B148. 
22. 
Kessler L, Wang S, Guo X, et al. Abstract 4496: INK128, an orally active TORC1/2 kinase 
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agents. Cancer research. 2010;70:4496. 
23. 
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cyclin-dependent kinases associated with low-dose paclitaxel-induced sub-G1 apoptosis. 
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26. 
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28. 
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29. 
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30. 
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associated with histologic subtypes and are predictive of sensitivity to PI3K inhibitors in lung 
cancer preclinical models. Clinical cancer research : an official journal of the American 
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Voss M, Gordon MS, Mita M, et al. Phase I study of investigational oral mTORC1/2 inhibitor 
MLN0128: Expansion phase in patients with renal, endometrial, or bladder cancer. ESMO poster. 
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Ghobrial IM, Siegel DS, Vij R, et al. 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 Waldenstrom's macroglobulinemia. Am J 
Hematol. 2016;91:400-405. 
33. 
Zohren F. Takeda presents "Inhibiting the mTOR Complex: Biology and Targets" at the 14th 
International Kidney Cancer Symposium. In: Zohren F, ed. Oncology Tube2015. 
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Guimarães IS, Tessarollo NG, Lyra-Júnior PCM, et al. Targeting the PI3K/AKT/mTOR Pathway 
in Cancer Cells: InTech; 2015. 
35. 
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38. 
Kim SH, Juhnn YS, Song YS. Akt involvement in paclitaxel chemoresistance of human ovarian 
cancer cells. Ann N Y Acad Sci. 2007;1095:82-89. 
39. 
Sun H, Yu T, Li J. Co-administration of perifosine with paclitaxel synergistically induces 
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40. 
Hou H, Zhang Y, Huang Y, et al. Inhibitors of phosphatidylinositol 3'-kinases promote mitotic 
cell death in HeLa cells. PloS one. 2012;7:e35665. 
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Bretscher M, Rummans T, Sloan J, et al. Quality of life in hospice patients. A pilot study. 
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44. 
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Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: 
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47. 
Hyland ME, Sodergren SC. Development of a new type of global quality of life scale, and 
comparison of performance and preference for 12 global scales. Qual Life Res. 1996;5:469-480. 
48. 
PACLITAXEL - paclitaxel injection, solution [package insert]. Princeton, NJ: Sandoz; 2011. 
49. 
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50. 
Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am. J. Clin. Oncol. 1982;5:649-655. 
51. 
The Criteria Committee of New York Heart Association. Nomenclature and Criteria for 
Diagnosis of Diseases of the Heart and Great Vessels. 9 ed. Boston, MA: Little, Brown & Co; 
1994. 


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Appendix 1: 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):649-55.50 
 


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Appendix 2: 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 [32]. 


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Appendix 3: New York Heart Association Classification of Cardiac Disease 
 
Class 
Functional Capacity 
Objective Assessment 
I 
Patients with cardiac disease but without resulting limitations of No objective evidence of physical activity. 
Ordinary physical activity does not cause cardiovascular disease. Undue fatigue, palpitation, dyspnea, or anginal 
pain. 
II 
Patients with cardiac disease resulting in slight limitation of Objective evidence of minimal physical activity. 
They are comfortable at rest. Ordinary cardiovascular disease. Physical activity results in fatigue, palpitation, 
dyspnea, or anginal pain. 
III 
Patients with cardiac disease resulting in marked limitation of Objective evidence of moderately physical activity. 
They are comfortable at rest. Less than severe cardiovascular disease. ordinary activity causes fatigue, 
palpitation, dyspnea, or angina pain. 
IV 
Patients with cardiac disease resulting in inability to carry on Objective evidence of severe any physical 
activity without discomfort. Symptoms of heart cardiovascular disease. Failure or the anginal syndrome may 
be present even at rest. If any physical activity is undertaken, discomfort is increased. 
 
• 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; 1994:253-256.51 


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Appendix 4: 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 (e.g., 
high dose, double strength) or as a “moderate CYP3A inhibitor” when another preparation was used (e.g., low dose, 
single strength). 
 (b) Withdrawn from the United States market because of safety reasons. 


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Appendix 5: Guidelines for TAK-228/TAK-117 and Paclitaxel Dose Modification and Delay 
 
Table Guidelines for TAK-228/TAK-117 and Paclitaxel Dose Modification and Delay (after 
cycle 1 only) 
Please refer to MLN0128 dose changes in the following tables to include both TAK-228 and TAK-117.  
 
 


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Table Guidelines for TAK-228/TAK-117 and Paclitaxel Dose Modification and Delay  
 
 
 
 


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Table Guidelines for TAK-228/TAK-117 and Paclitaxel Dose Modification and Delay (> cycle 1) 
 
 
 
 
 
 
>6 x ULN) 
Please refer to recommended labs, listed under Grade 2. This is per investigator’s discretion. 


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 APPENDIX 6: HEALTH RELATED QUALITY OF LIFE  
HEALTH-RELATED QUALITY OF LIFE (HRQOL), LINEAR ANALOGUE SELF 
ASSESSMENT (LASA)  
Patient Name: _______________________________ 
Date: ______________________ 
Patient Number:  ______________________________ 
 
 
Directions: Please circle the number (0-10) best reflecting your response to the following 
that describes your feelings during the past week, including today. 
How would you describe: 
 
1. your overall Quality of Life? 
 
 
0 
1 2 
3 
4 
5 
6 
7 
8 
9 
10   
 
As bad as  
 
 
 
 
 
 
 
 
As good as 
 
it can be  
 
 
 
 
 
 
 
 
it can be 
 
2. your overall mental (intellectual) well being? 
 
 
0 
1 2 
3 
4 
5 
6 
7 
8 
9 
10   
 
As bad as  
 
 
 
 
 
 
 
 
As good as 
 
it can be  
 
 
 
 
 
 
 
 
it can be 
 
3. your overall physical well being? 
 
 
0 
1 2 
3 
4 
5 
6 
7 
8 
9 
10   
 
As bad as  
 
 
 
 
 
 
 
 
As good as 
 
it can be  
 
 
 
 
 
 
 
 
it can be 
 
4. your overall emotional well being? 
 
 
0 
1 2 
3 
4 
5 
6 
7 
8 
9 
10   
 
As bad as  
 
 
 
 
 
 
 
 
As good as 
 
it can be  
 
 
 
 
 
 
 
 
it can be 
 
5. your level of social activity? 
 
 
0 
1 2 
3 
4 
5 
6 
7 
8 
9 
10   
 
As bad as  
 
 
 
 
 
 
 
 
As good as 
 
it can be  
 
 
 
 
 
 
 
 
it can be 
 
6. your overall spiritual well being? 
 
 
0 
1 2 
3 
4 
5 
6 
7 
8 
9 
10   
 
As bad as  
 
 
 
 
 
 
 
 
As good as 
 
it can be 
it can be 
 
 
 
 
 


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APPENDIX 7: THERAPY RELATED SYMPTOMS CHECKLIST  
THERAPY-RELATED SYMPTOMS CHECKLIST (TRSC) 
Name:                                                              Hospital #                   Date:            
  
PLEASE CHECK THE PROBLEMS YOU HAVE HAD IMMEDIATELY AFTER AND SINCE 
YOUR  LAST  TREATMENT.    PLEASE  CIRCLE  HOW  SEVERE  THE  PROBLEM  WAS 
ACCORDING TO THE FOLLOWING SCALE:  
  
0 = NONE          1 = MILD         2 = MODERATE         3 = SEVERE             4 = VERY SEVERE  
 CHECK  
  
EXAMPLE  
Pain  
Degree of Severity (CIRCLE)  
0  
1  
2  
  
4  
  
Taste Change  
0  
1  
2  
3  
4  
  
Loss of appetite  
0  
1  
2  
3  
4  
  
Nausea  
0  
1  
2  
3  
4  
  
Vomiting  
0  
1  
2  
3  
4  
  
Weight loss  
0  
1  
2  
3  
4  
  
Sore mouth  
0  
1  
2  
3  
4  
  
Cough  
0  
1  
2  
3  
4  
  
Sore throat  
0  
1  
2  
3  
4  
  
Difficulty swallowing  
0  
1  
2  
3  
4  
  
Jaw pain  
0  
1  
2  
3  
4  
  
Shortness of breath  
0  
1  
2  
3  
4  
  
Numbness in fingers and/or toes  
0  
1  
2  
3  
4  
  
Feeling sluggish  
0  
1  
2  
3  
4  
  
Depression  
0  
1  
2  
3  
4  
  
Difficulty concentrating  
0  
1  
2  
3  
4  
  
Fever  
0  
1  
2  
3  
4  
  
Bruising  
0  
1  
2  
3  
4  
  
Bleeding  
0  
1  
2  
3  
4  
  
Hair loss  
0  
1  
2  
3  
4  
  
Skin changes  
0  
1  
2  
3  
4  
  
Soreness   in   vein   where   chemotherapy  
was given  
0  
1  
2  
3  
4  
  
Difficulty sleeping  
0  
1  
2  
3  
4  
  
Pain  
0  
1  
2  
3  
4  
  
Decreased interest in sexual activity  
0  
1  
2  
3  
4  
  
Constipation  
0  
1  
2  
3  
4  
 
Other problems (please list below)  
  
  
  
  
  
  
0  
1  
2  
3  
4  
  
0  
1  
2  
3  
4  
  
0  
1  
2  
3  
4  
  
0  
1  
2  
3  
4  


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Phoebe D. Williams, PhD ©Copyright 1995 University of Kansas Medical Center