Conditions: Hepatocellular Carcinoma Liver Cancer HCC
Keywords: MLN0128 Sapanisertib TORC1/2 inhibitor INK128 Nexavar Sorafenib
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 11
Healthy volunteers: no

Brief summary:
This is an open label, multi-center, randomized phase I/II study of MLN0128 versus standard sorafenib. Eligible subjects in the phase I trial will receive MLN0128 in escalating doses. Eligible subjects in the phase II trial will be 1:1 randomized to either the MLN0128 arm or the sorafenib arm.

Detailed description:
OUTLINE: This is a multi-center trial.

The phase 1 dose escalation trial will evaluate MLN0128 in a standard 3+3 successive cohort design to identify the highest planned dose level. Phase II trial subjects will be 1:1 randomized to receive either MLN0128 (investigational arm) or sorafenib (control arm).

PHASE I DOSE ESCALATION INVESTIGATIONAL TREATMENT:

Cohort 1 (dose level +1) will consist of 3-6 evaluable patients who will receive MLN0128 15mg on day 1 of the 28-day cycle.

Cohort 2 (dose level +2) will consist of 3-6 evaluable patients who will receive MLN0128 20mg on day 1 of the 28-day cycle.

Cohort 3 (dose level +3) will consist of 3-6 evaluable patients who will receive MLN0128 30mg on day 1 of the 28-day cycle.

Subjects will be evaluated for dose limiting toxicity (DLT) in the first 28 days of treatment (1 cycle). However, decisions to move to next dose escalation cohort will not be made until all subjects complete 2 cycles of therapy at a given dose. There will be no further dose escalation beyond dose level +3.

PHASE II INVESTIGATIONAL TREATMENT:

Randomization will take place following completion of the screening evaluations and eligibility assessments. Stratification factors will be employed during randomization to minimize between-arm assignment imbalance.

* 1 Child-Pugh score 5-6
* 2 Child-Pugh score 7

Within the strata, subjects will be randomly assigned with equal probability to either the investigational arm (Arm A: MLN0128) or the control arm (Arm B: sorafenib).

Arm A: MLN0128 will be administered orally at the recommended phase II dose (RP2D) once weekly.

Arm B: Sorafenib will be administered at 400mg PO BID daily, with dose adjustment per standard of care.

A new treatment cycle (1 cycle = 28 days) will only be initiated when all of the following conditions are met:

* Absolute neutrophil count (ANC) ≥ 1.5 x 10\*9/L
* Platelets ≥ 50 x 10\*9/L
* Non-hematologic treatment related toxicities have improved to grade 1 or resolved per Common Terminology Criteria for Adverse Events v4.0 (CTCAE)

Treatment may continue until progression, unacceptable toxicity, or withdrawal from study.

Estimated Life Expectancy: ≥ 3 months

Subjects must have adequate organ function, as specified below, within 7 days before study registration:

Bone marrow reserve consistent with:

* Absolute neutrophil count (ANC) ≥ 1.5 x 10\*9/L
* Platelet count ≥ 50 x 10\*9/L
* Hemoglobin ≥ 9 g/dL

Hepatic:

* Total bilirubin ≤ 2 x upper limit of normal (ULN)
* Transaminases (aspartate aminotransferase (AST), serum glutamic oxaloacetic transaminase (SGOT) and alanine aminotransferase (ALT), serum glutamic pyruvic transaminase (SGPT) ≤ 5 x ULN

Renal:

* Creatinine clearance ≥50 mL/min based either on Cockcroft-Gault estimate or based on urine collection (12 or 24 hour)

Metabolic:

* Fasting serum glucose (≤ 130 mg/dL) and fasting triglycerides ≤ 300 mg/dL.
* Glycosylated hemoglobin (HbA1c) \<7.0%

Arms:
arm 1: Subjects will receive MLN0128 orally on days 1, 8, 15 and 22 in successive cohorts.

Cohort 1 MLN0128 15mg each week (QW); Cohort 2 MLN0128 20mg QW; Cohort 3 MLN0128 30mg QW arm 2: Subjects randomized to experimental arm will receive MLN0128 orally at the recommended phase II dose (RP2D) once weekly. arm 3: Subjects randomized to control arm will receive sorafenib 400mg by mouth (PO) twice a day (BID) daily.

Interventions: intervention 1: MLN0128 intervention 2: MLN0128 (RP2D) intervention 3: Sorafenib
Intervention descriptions: intervention 1: Phase I Dose Escalation Study Cohort 1 MLN0128 15mg QW; Cohort 2 MLN0128 20mg QW; Cohort 3 MLN0128 30mg QW intervention 2: Phase II Arm A:

MLN0128 administered orally at the recommended phase II dose (RP2D) once weekly. intervention 3: Phase II Arm B:

Sorafenib administered at 400mg PO BID daily

Protocol document:
Prot_SAP_000.pdf: 
 
1 
 
 
An Open Label Randomized Phase I/II Trial of TAK-228 Compared to Sorafenib in 
Patients with Advanced or Metastatic Hepatocellular Carcinoma: Big Ten Cancer 
Research Consortium BTCRC-GI13-002 
 
 
Sponsor-Investigator 
Bert O’Neil, MD 
Indiana University Melvin and Bren Simon Cancer Center 
 
 
Co-Investigators  
Neeta K. Venepalli, MD, MBA 
University of Illinois Cancer Center 
 
Dustin Deming, MD 
University of Wisconsin Carbone Cancer Center 
 
Vahid Yaghmai, MD, MS 
Northwestern University-Feinberg School of Medicine 
 
Statistician 
Susan M. Perkins, PhD 
Indiana University School of Medicine 
 
 
Trial Supported by  
Millennium Pharmaceuticals 
(IISR-2014-100530) 
 
Trial Management by 
BTCRC Administrative Headquarters at Hoosier Cancer Research Network 
500 North Meridian Street, Suite 100 
Indianapolis, IN 46204 
 
Investigational New Drug (IND) Application #   
128501 
 
 
Initial Protocol Version Date: 10NOV2015 
 
Amendment Version Date:  
28NOV2016 
13NOV2017 (current) 
 
 


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PROTOCOL SIGNATURE PAGE  
 
An Open Label Randomized Phase I/II Trial of TAK-228 Compared to Sorafenib in  
Patients with Advanced or Metastatic Hepatocellular Carcinoma:  
Big Ten Cancer Research Consortium BTCRC-GI13-002 
 
VERSION DATE:  13NOV2017 
I confirm I have read this protocol, I understand it, and I will work according to this protocol and to 
the ethical principles stated in the latest version of the Declaration of Helsinki, the applicable 
guidelines for good clinical practices, or the applicable laws and regulations of the country of the 
study site for which I am responsible, whichever provides the greater protection of the individual. I 
will accept the monitor’s overseeing of the study. I will promptly submit the protocol to applicable 
ethical review board(s). 
 
 
 
 
 
 
 
 
 
____________________________________ 
________________________ 
 Signature of Investigator 
 
 
 
 
 
       Date 
 
 
____________________________________ 
 Investigator Name (printed) 
 
 
____________________________________ 
 Investigator Title 
 
 
____________________________________ 
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____________________________________ 
 Not Submitting to IRB 
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PLEASE COMPLETE AND EMAIL TO BTCRC ADMINISTRATIVE HEADQUARTERS  
Instructions to the investigator:  Please SIGN and DATE this signature page. 
PRINT your name and title, the name and location of the facility in which the 
study will be conducted, and the expected IRB approval date. Scan and email 
the completed form to BTCRC Administrative Headquarters and keep a record 
for your files. 


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STUDY SYNOPSIS 
 
TITLE 
An Open Label Randomized Phase I/II Trial of TAK-228 Compared to 
Sorafenib in Patients with Advanced or Metastatic Hepatocellular 
Carcinoma: Big Ten Cancer Research Consortium BTCRC-GI13-002
PHASE  
I/II 
TOTAL  
NUMBER OF 
SUBJECTS 
Phase I: up to 18 subjects 
Phase II: 100 subjects 
OBJECTIVES 
Phase I: 
Primary Objective: 
The Primary objective of this prospective, open label, dose escalation study is to 
determine the maximum tolerated dose (MTD) of TAK-228. 
 
Secondary Objectives: 
1. Characterize adverse effects (AE) 
2. Measure overall survival (OS) 
3. Evaluate time to progression (TTP) 
4. Measure progression-free survival (PFS) 
5. Determine objective response rate (ORR) and disease control rate (DCR) at 16 
and 24 weeks 
 
Phase II: 
Primary Objective:  
The primary objective of this prospective, open label, randomized study is to 
evaluate time to progression (TTP) associated with TAK-228 in the first line 
setting of advanced hepatocellular carcinoma (HCC), compared to a control arm 
treated with sorafenib. 
 
Secondary Objectives: 
1. Measure overall survival (OS) 
2. Measure progression-free survival (PFS) 
3. Characterize adverse effects (AE) 
4. Determine objective response rate (ORR) and disease control rate (DCR) at 16 
and 24 weeks 
 
Correlative Objectives: 
1. Assess pharmacokinetics (PK) of TAK-228 
2. Evaluate mTOR and PI3K/Akt expression and phosphoproteins via 
immunohistochemistry (IHC)  
3. Characterize oncogene expression affecting mTOR activation via targeted 
deep sequencing assay  
4. Assess tumor necrosis and modified RECIST (mRECIST) criteria 
STUDY DESIGN 
This will be an open-label, randomized phase I dose escalation trial followed by a 
phase II clinical trial.  
Eligible subjects in the phase I trial will receive TAK-228 in escalating doses. 


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Eligible subjects in the phase II trial will be 1:1 randomized to either TAK-228 or 
sorafenib arm. Block randomization stratified by Child-Pugh (CP) score (5-6 vs. 
7) will be adopted with varying block sizes.
KEY 
ELIGIBILITY 
CRITERIA  
1. Measurable advanced or metastatic HCC. Phase II subjects only: tissue biopsy 
will be required prior to registration if HCC archived tissue is not available for 
correlative studies. Advanced HCC is defined as disease not amenable to surgery, 
ablation, transplant, or embolic therapy. 
2. Prior locoregional liver directed therapy is permitted, as long as treatment was ≥ 
6 weeks prior to study entry, and demonstration of progression per RECIST v1.1 
3. ECOG PS 0-1-2 
4. Child-Pugh Score ≤7 
5. No systemic therapy allowed for the phase II cohort. No restrictions for prior 
systemic therapy for the phase I cohort; phase I patients may also be treatment 
naïve. 
OUTCOME 
MEASURES 
Phase I: 
Primary Endpoint: The primary endpoint is determination of the maximum 
tolerated dose (MTD) for TAK-228.  MTD is defined as the dose level at which 
fewer than 33% of subjects experience a dose limiting toxicity (DLT). 
 
Secondary Endpoints: 
1. Adverse effects (AE) as defined by CTCAE v4. 
2. Overall Survival (OS) as defined by the time from randomization to date of 
death from any cause. 
3. Time to progression is defined as the time from randomization until tumor 
progression as defined by RECIST v1.1. 
4. Progression free survival (PFS) as defined as time from randomization to 
tumor progression or death from any cause. 
5. Objective Response Rate (ORR) defined as complete response (CR)+partial 
response (PR) and Disease Control Rate (DCR), as a sum of stable disease (SD 
for 8 weeks or longer), partial response (PR), and complete response (CR), as 
defined by RECIST v1.1. 
 
Phase II: 
Primary Endpoint: The primary endpoint is evaluation of time to progression, 
which is defined as the time from randomization until tumor progression as 
defined by RECIST v1.1. 
 
Secondary Endpoints: 
1. Overall Survival (OS) as defined by the time from randomization to date of 
death from any cause. 
2. Progression free survival (PFS) as defined as time from randomization to 
tumor progression or death from any cause. 
3. Adverse effects (AE) as defined by CTCAE v4. 
4. Objective Response Rate (ORR) defined as complete response (CR)+partial 
response (PR) and Disease Control Rate (DCR), as a sum of stable disease (SD 
for 8 weeks or longer), partial response (PR), and complete response (CR), as 
defined by RECIST v1.1.


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Correlative Endpoints: 
1. Assess Pharmacokinetics (PK) in first 10 subjects in TAK-228 arm (Arm A). 
2. Evaluate mTOR and PI3K/Akt expression and phosphoproteins via 
immunohistochemistry (IHC) of phosphorylated Akt, 4EBP1, S6 kinase, and 
ERK1/2. 
3. Characterize oncogene expression affecting mTOR activation via targeted 
deep sequencing assay designed to interrogate genes commonly mutated in 
human cancers. 
4. Assess tumor necrosis and modified RECIST (mRECIST) criteria
STATISTICAL 
CONSIDERATIONS 
Phase I:  
The primary endpoint for this Phase I study is MTD.  We will establish that dose is 
safe if we observe less than a 33% chance for DLT at a given dose level during the 
first cycle of therapy. A conventional 3x3 design will be utilized. 
 
Phase II: 
Therapy with sorafenib in subjects with Child-Pugh A (CPA) cirrhosis was 
associated with a median TTP of 5.5 months. Given inclusion of CP 7 subjects 
(technically CPB), we would anticipate a median TTP of 12 weeks for sorafenib. 
In this study, we assume that TAK-228 will increase TTP from 50% to 70% at 
week 12. A 10% dropout rate is expected for the sorafenib arm and a similar 
dropout pattern is expected for the TAK-228 arm. Enrollment is expected to be 
completed in 24 months. Subjects will be followed for a total of 2 years after 
progression. Two-sided log-rank test will be used to compare TTP at type I error 
level 0.05. Consequently, N=44 subjects per group are required to obtain a power 
level of 0.80. We further adjust the sample size to N=50 per group to account for 
potentially unevaluable subjects. 
 
Analyses will include Kaplan-Meier curves and log-rank tests for TTP, OS, and 
PFS, and exact binomial confidence intervals and chi-square or Fisher Exact tests 
for ORR, DCR, and adverse events. For OS, Cox regression will be used to 
evaluate the effects of oncogenic abnormalities on survival times. 
ENROLLMENT 
PERIOD 
Enrollment period 24 months 
TOTAL STUDY 
DURATION  
Estimated accrual: 5 subjects per month 
 
Estimated total duration of study: 42 months
 


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INDEX  
 
SECTION                                                                                                                 
PAGE 
LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS ................................................... 8 
PHASE I SCHEMA ....................................................................................................................... 10 
PHASE II SCHEMA...................................................................................................................... 11 
1 
BACKGROUND & RATIONALE ....................................................................................... 12 
1.1 
Scientific Background ........................................................................................................... 12 
1.2 
Nonclinical Summary ........................................................................................................... 15 
1.3 
Clinical Experience with TAK-228 ...................................................................................... 17 
1.4 
Updated Manufacturing Process ........................................................................................... 19 
1.5 
Clinical Summary of Safety .................................................................................................. 19 
1.6 
Study Rationale ..................................................................................................................... 21 
2 
OBJECTIVES AND ENDPOINTS ....................................................................................... 22 
2.1 
Phase I Objectives ................................................................................................................. 22 
2.2 
Phase II Study Objectives ..................................................................................................... 22 
2.3 
Phase I Study Endpoints ....................................................................................................... 23 
2.4 
Phase II Study Endpoints ...................................................................................................... 23 
3 
ELIGIBILITY CRITERIA .................................................................................................... 24 
3.1 
Inclusion Criteria .................................................................................................................. 24 
3.2 
Exclusion Criteria ................................................................................................................. 25 
4 
SUBJECT REGISTRATION ................................................................................................ 27 
5 
STUDY DESIGN AND TREATMENT PLAN .................................................................... 27 
5.1 
Overview of Study Design .................................................................................................... 27 
5.2 
Number of Subjects............................................................................................................... 27 
5.3 
Duration of Study .................................................................................................................. 27 
5.4 
Phase I Dose Escalation Study .............................................................................................. 28 
5.5 
Phase II Study ....................................................................................................................... 30 
5.6 
Criteria for administration of subsequent treatment cycles .................................................. 31 
5.7 
Pre-medication ...................................................................................................................... 31 
5.8 
Drug Administration ............................................................................................................. 31 
5.9 
Supportive Care .................................................................................................................... 32 
5.10  Excluded Concomitant Medications and Procedures ........................................................... 32 
5.11  Permitted Concomitant Medications and Procedures ........................................................... 33 
5.12  Precautions and Restrictions ................................................................................................. 34 
6 
DOSE MODIFICATIONS ..................................................................................................... 34 
6.1 
Treatment-Limiting Adverse Events ..................................................................................... 35 
6.2 
TAK-228 Dose Modifications .............................................................................................. 35 
6.3 
Management of TAK-228 Clinical Events ........................................................................... 36 
6.4 
Sorafenib Dose Modifications .............................................................................................. 43 
6.5 
Management of Sorafenib Clinical Events ........................................................................... 43 
7 
STUDY CALENDAR & EVALUATIONS .......................................................................... 45 
7.1 
Screening............................................................................................................................... 48 
7.2 
On Treatment ........................................................................................................................ 48 
7.3 
Off Treatment........................................................................................................................ 52 
7.4 
Follow-up (±14 days) ............................................................................................................ 53 
8 
CRITERIA FOR DISEASE EVALUATION ...................................................................... 53 


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8.1 
Definitions Associated with RECIST version 1.1 [Eur J Ca 45:228-247, 2009]. ................ 53 
8.2 
Response Criteria .................................................................................................................. 54 
8.3 
Evaluation of best overall response ...................................................................................... 55 
8.4 
Definitions for Response Evaluation –RECIST version 1.1 ................................................. 56 
8.5 
Methods of Measurement ..................................................................................................... 57 
8.6 
mRECIST for HCC: Assessment of Tumor Lesions at Baseline ......................................... 58 
8.7 
mRECIST: Defining Treatment Response and Tumor Progression ..................................... 59 
8.8 
mRECIST: Overall Response Assessment ........................................................................... 64 
9 
BIOLOGICAL CORRELATIVES ....................................................................................... 64 
9.1 
Evaluate mTOR and PI3K/Akt expression and phosphoproteins. ........................................ 64 
9.2 
Characterize oncogene expression affecting mTOR activation. ........................................... 65 
9.3 
Assess tumor necrosis and modified RECIST (mRECIST) criteria ..................................... 65 
9.4 
Samples for future studies ..................................................................................................... 65 
10 
DRUG INFORMATION .................................................................................................... 66 
10.1  TAK-228 ............................................................................................................................... 66 
10.2  Sorafenib ............................................................................................................................... 70 
11 
ADVERSE EVENTS .......................................................................................................... 73 
11.1  Definitions............................................................................................................................. 73 
11.2  Reporting............................................................................................................................... 75 
11.3  Serious Adverse Event (SAE) Reporting .............................................................................. 75 
11.4  BTCRC AHQ Requirements for Reporting SAEs to FDA ................................................... 77 
11.5  IND Safety Reports Unrelated to This Trial ......................................................................... 78 
12 
STATISTICAL CONSIDERATIONS .............................................................................. 78 
12.1  General Considerations ......................................................................................................... 78 
12.2  Study Design ......................................................................................................................... 78 
12.3  Analysis Datasets .................................................................................................................. 79 
12.4  Sample Size/Accrual/Study Duration/Replacement Rules ................................................... 79 
12.5  Subject Characteristics and Significant Protocol Violations ................................................ 79 
12.6  Concomitant Medication ....................................................................................................... 80 
12.7  Disposition ............................................................................................................................ 80 
12.8  Exposure/Compliance ........................................................................................................... 80 
12.9  Analysis of Primary Objectives/Aims .................................................................................. 80 
12.10 
Analysis of Secondary Objectives/Aims ........................................................................... 80 
12.11 
Tertiary/Exploratory/Correlative Endpoints (Phase II subjects only) ............................... 81 
12.12 
Interim Analysis ................................................................................................................ 81 
13 
TRIAL MANAGEMENT ................................................................................................... 82 
13.1  Quality Controls and Quality Assurance .............................................................................. 82 
13.2  Data Handling and Record Keeping ..................................................................................... 83 
13.3  Confidentiality ...................................................................................................................... 84 
13.4  Changes to the Protocol and Informed Consent ................................................................... 84 
13.5  Ethics..................................................................................................................................... 85 
14 
REFERENCES .................................................................................................................... 87 
 


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LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS 
Abbreviation 
Term 
4E-BP1 
eukaryotic initiation factor eIF4E-binding protein 1 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
aPTT 
activated partial thromboplastin time 
ASCO 
American Society of Clinical Oncology 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BID 
bis in die; twice a day 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CRP 
C-reactive protein 
CYP 
cytochrome P450 
DLT 
dose-limiting toxicity 
DTC 
differentiated thyroid carcinoma 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EOT 
End of Treatment (visit) 
GBM 
glioblastoma multiforme 
Hb 
Hemoglobin 
HCC 
hepatocellular carcinoma 
Hct 
Hematocrit 
HFSR 
hand-foot skin reaction 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
IRB 
institutional review board 
LDH 
lactate dehydrogenase 
LFT 
liver function test(s) 
MTD 
maximum tolerated dose 
mTOR 
mammalian target of rapamycin 
mTORC1 
mTOR complex 1 
mTORC2 
mTOR complex 2 


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Abbreviation 
Term 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for 
Adverse Events 
NSCLC 
non-small cell lung cancer 
NYHA 
New York Heart Association 
OCT 
organic cation transporter 
OS 
overall survival 
PDGF 
platelet-derived growth factor 
PFS 
progression free survival 
PI3K 
phosphoinositide 3-kinase 
PK 
pharmacokinetic(s) 
PO 
per os; by mouth (orally) 
PTEN 
phosphatase and tensin homolog 
QD 
quaque die; every day 
QTc 
rate-corrected QT interval (milliseconds) of electrocardiogram 
RCC 
renal cell carcinoma 
S6K1 
ribosomal protein S6 kinase 
SAE 
serious adverse event 
TSH 
thyroid stimulating hormone 
VEGF 
vascular endothelial growth factor 
 
 
 


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PHASE I SCHEMA 
 
An Open Label Randomized Phase I/II Trial of TAK-228 Compared to Sorafenib in Patients with 
Advanced or Metastatic Hepatocellular Carcinoma: Big Ten Cancer Research Consortium 
BTCRC-GI13-002 
 
 
 
 
 
 
 
 
 
 
 
1: TAK-228 escalating cohorts: 15mg, 20mg, and 30mg PO q week. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligible Patients with Advanced or Metastatic Hepatocellular Carcinoma, 
No restrictions for number of prior systemic therapies;  
patients may also be treatment naïve 
 Subsequent cohorts enrolled after 1 cycle 
 Treatment may continue until progression, 
unacceptable toxicity, or withdrawal from study. 
Follow Up 
 
If treatment ended for reasons other than disease progression, follow 
every 3 months for 1 year, then every 6 months until progression.  
 
After disease progression, report survival status every 6 months until 
2 years after progression. 
TAK-228 at assigned dose1 
given on Days 1, 8, 15, 22 
every 28 days
 
Repeat scans every 2 cycles 
 
Treatment may continue 
until progression, 
unacceptable toxicity, or 
withdrawal from study. 


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PHASE II SCHEMA 
 
An Open Label Randomized Phase I/II Trial of TAK-228 Compared to Sorafenib in Patients with 
Advanced or Metastatic Hepatocellular Carcinoma: Big Ten Cancer Research Consortium 
BTCRC-GI13-002 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*RP2D: recommended Phase II dose 
 
 
Eligible Patients with Advanced or Metastatic Hepatocellular Carcinoma 
Stratify 
Child-Pugh score 5-6 vs. Child-Pugh score 7 
Arm A  
TAK-228 at RP2D* PO 
Days 1, 8, 15, 22 
Arm B 
Sorafenib 400mg PO BID 
Daily 

Repeat cycles q28 days 

Scans every 8 weeks  

Treatment may continue 
until progression, 
unacceptable toxicity, or 
withdrawal from study. 
Randomize 
Follow Up 

If treatment ended for reasons other than disease progression, follow 
every 3 months for 1 year, then every 6 months until progression.  

After disease progression, report survival status every 6 months until 
2 years after progression. 


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1 
BACKGROUND & RATIONALE 
 
1.1 
Scientific Background 
 
1.1.1 Disease Under Treatment 
 Pathologically confirmed hepatocellular carcinoma (HCC) not amenable to liver 
transplantation 
o Locally advanced, unresectable, or metastatic disease 
 At least 1 lesion accurately measured in ≥ 1 dimension according to RECIST v1.1 criteria  
 
1.1.2 Introduction 
Hepatocellular carcinoma (HCC) is the sixth most common malignancy worldwide, and the third 
most common cause of global cancer related mortality1,2. Prognostic and therapeutic options are 
dependent upon the severity of underlying liver disease, and median overall survival (OS) for 
metastatic or locally advanced disease is estimated at 5-8 months. HCC is relatively refractory to 
cytotoxic chemotherapy, likely due to over expression of multidrug resistant genes3, protein 
products such as heat shock 704 and P-glycoprotein5, and p53 mutations. Presently, systemic 
therapeutic options in the locally advanced or metastatic setting are limited to sorafenib, an oral 
multikinase inhibitor targeting Raf kinase, vascular endothelial growth factor (VEGF), and 
platelet-derived growth factor (PDGF) receptor tyrosine kinase signaling.  
 
1.1.3. Systemic Therapy for Advanced HCC 
Sorafenib was approved on the basis of two randomized, placebo-controlled, phase III studies6,7 
demonstrating significant improvement in overall survival (OS), progression free survival (PFS), 
and a manageable toxicity profile. In the SHARP trial7, median survival improved by 2.8 months 
with sorafenib in comparison to placebo (10.7 months vs. 7.9 months; hazard ratio [HR], 0.69; 
95% confidence interval [CI], 0.55–0.87; p < 0.001), while in the Asia-Pacific trial6, median OS 
improved by 2.3 months with sorafenib in comparison to placebo (6.5 months vs. 4.2 months; HR, 
0.68; 95% CI, 0.50–0.93; p = 0.014). Despite low response rates in both studies (respectively, 2%; 
3%), the median time to progression almost doubled in both studies (SHARP: 2.8 months to 5.5 
months (p < 0.001); Asia-Pacific: 1.4 months to 2.8 months, p<0.001). Since the approval of 
sorafenib in 2007, no additional agents have been FDA approved for HCC treatment. There is an 
urgent and unmet need for new therapeutic options for first and second line treatment of advanced 
HCC.   
 
1.1.4 The mTOR Signaling Pathway and HCC 
The mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase belonging to the 
phosphoinositide 3-kinase (PI3K)-related kinase family, and is implicated in cellular proliferation, 
angiogenesis, growth, and lipid metabolism8. mTOR is present in two multiprotein complexes, 
mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2).  
 
Signaling molecules upstream of mTORC1 include phosphatase and tensin homolog (PTEN), 
tuberous sclerosis complex (TSC proteins), adenosine monophosphate kinase (AMPK), the Rag 
guanosine triphosphatases (GTPases), and PI3K/Akt. mTORC1 is comprised of mTOR, 
mammalian LST8 (mLST8), DEPTOR, regulatory-associated protein of mTOR (RAPTOR), and 
proline-rich Akt substrate 40kDa (PRAS40). mTORC1 is activated by multiple inputs including 
the Wnt pathway, proinflammatory cytokines, and growth factors; growth factors including insulin 


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and insulin-like growth factor 1 activate mTORC1 via PIK3-Akt and Ras-Raf-MEK-ERK 
signaling pathways9. mTORC1 activation results in phosphorylation of two downstream mTOR 
pathway proteins, ribosomal protein S6 kinase (S6K1) and the eukaryotic initiation factor eIF4E-
binding protein 1 (4E-BP1), both of which are involved in protein translation resulting in cell 
growth, angiogenesis, and proliferation10. In addition to protein synthesis and lipogenesis, 
mTORC1 activation also results in autophagy inhibition and lysosome biogenesis9.  
 
mTORC2 is comprised of mTOR, mLST8, DEPTOR, PROTOR, RICTOR, and mSIN1; mTORC2 
phosphorylates Akt at Ser473, and is implicated in actin cytoskeleton organization, cell migration, 
survival, and proliferation8. 
 
mTORC1 and mTORC2 pathways are upregulated in 40-50% of HCC11, and mTOR activation in 
HCC is associated with deregulation of multiple pathways including EGF, IGF, and PTEN12, and 
early recurrence, poor differentiation, and worse prognosis12,13. Notably, mTOR pathway 
activation is largely dependent on ligand dependent receptor activation; recent studies utilizing 
PCR12 and next generation sequencing14-16 report low frequency of alterations of copy number or 
somatic mutations of PTEN, mTOR, PIK3CA. Evaluation of the mTOR signaling pathway in 351 
human HCC samples revealed abnormalities affecting mTOR signaling (as evaluated by p-RPS6 
immunohistochemistry) in about half of the patients and was associated with worse outcome12. 
mTOR activation may also be implicated in sorafenib resistance; high expression of ribosomal S6 
phosphorylated at serine residue 235/236 was found to be significantly correlated with the 
resistance of HCC cells to sorafenib17.  
 
1.1.5 mTOR Inhibitors in HCC 
 
1.1.5.1 First generation mTOR inhibitors 
mTORC1 is the target for the macrolide antibiotic rapamycin (sirolimus), and is inhibited by a 
complex of rapamycin and FKBP12 protein. First generation mTOR inhibitors include rapamycin 
and rapalog derivatives including everolimus, temsirolimus, deforolimus (or ridaforolimus), and 
Nab-rapamycin9.   
Several in vitro and in vivo preclinical studies support rapalog efficacy in inhibiting HCC tumor 
growth;  in human HCC cell lines, sirolimus, everolimus, and temsirolimus demonstrated 
successful inhibition of cell growth and proliferation10,12,14,18-20, while in HCC mouse and rat 
models, sirolimus and everolimus reduced tumor volume and increased survival in comparison to 
controls10,12,14,18-21. 
Rapalog efficacy is under evaluation in active clinical trials in multiple HCC settings, including 
adjuvant therapy post liver transplant, adjuvant therapy post transcatheter arterial 
chemoembolization (TACE), and advanced HCC both first and second line (single agent, and in 
combination with other biologics)9. Rapamycin analogs utilized in the post-transplant 
immunosuppressive setting have been demonstrated to reduce risk of HCC recurrence22-28 and 
improve survival24 in case reports and retrospective reports. The combination of sirolimus and 
sorafenib for HCC recurrence post-transplant demonstrated efficacy with improved survival and 
time to progression in two small retrospective analysis29,30, while two case studies reported partial 
or complete response for subjects with HCC recurrence post-transplant31,32. However, prospective 
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Rapalog efficacy in the advanced HCC setting is uncertain; phase II studies of first line sirolimus 
demonstrated median OS 6.1 months, and a disease control rate of 43%33. A phase III study of 
second line everolimus following sorafenib failure failed to show survival benefit for everolimus 
in comparison with best supportive care (median OS 7.6 vs. 7.3 mos.; HR 1.05, 95% CI [0.86-
1.27]; p=0.675)34.  
1.1.5.2 Second Generation mTOR inhibitors in HCC 
Rapalog efficacy may be limited due to three reasons: 1) mTORC1 inhibition results in 
upregulation/activation of PI3K-Akt with MAPK and RAS signaling, likely potentiating 
tumorigenesis; 2) mTORC1 blockage results in inhibition of cell growth and not cell death; 
3) mTORC2 is not inhibited by rapalogs9. Additionally, recent studies showed that rapamycin 
inhibited only S6K1, but did not impact 4EBP1 phosphorylation and cap-dependent translation.  
Second generation mTORC inhibitors are able to block phosphorylation of all targets of mTORC1 
and mTORC2 via competitive binding to the adenosine 5’ triphosphate (ATP) pocket on mTOR. 
MLN 0128 is such an inhibitor, which has recently undergone phase I evaluation in subjects with 
advanced solid and hematologic malignancies. Following establishment of the MTD (reported at 
ASCO 2012), subjects with select advanced, refractory solid tumors, including NSCLC, HCC, 
NET, GBM and breast were enrolled in expansion cohorts of up to 20 evaluable subjects. TAK-
228 was dosed at 45 mg once daily in 28-day cycles until disease progression. Encouraging 
signals of biomarker and clinical activity were observed in HCC and NSCLC. Due to the 
frequency of dose reductions and interruptions, 30 mg once daily is recommended for future 
studies 35. 
1.1.5 TAK-228  
Millennium has developed TAK-228, which is a novel, highly selective, orally bioavailable 
adenosine 5’ triphosphate (ATP)-competitive inhibitor of the serine/threonine kinase referred to as 
the mechanistic target of rapamycin (mTOR). TAK-228 (formerly MLN0128; INK128) targets 2 
distinct mTOR complexes, mTORC1 and mTORC2. 
 
TAK-228 selectively and potently inhibits mTOR kinase (IC50 = 1.1 nM), inhibits mTORC1/2 
signaling, and prevents cellular proliferation. The mTOR is a kinase that regulates cell growth, 
translational control, angiogenesis, and cell survival by integrating nutrient and hormonal signals. 
mTOR kinase plays a key role in several pathways that are frequently dysregulated in human 
cancer.36 mTORC1 is best known as a key regulator of protein translation through phosphorylation 
of 4EBP1 (the eukaryotic translation Initiation Factor 4E-binding Protein 1) and ribosomal protein 
S6 (known as S6) kinase. mTORC2 is best known for its ability to fully activate protein kinase B 
(Akt) by phosphorylation on the S473 site, which regulates proliferation and survival pathways37. 
 
The mTORC is an important therapeutic target that is a key intracellular point of convergence for 
a number of cellular signaling pathways. Inhibiting mTOR may inhibit abnormal cell 
proliferation,tumor angiogenesis, and abnormal cellular metabolism, thus providing the rationale 
for mTOR inhibitors as potential agents in the treatment of a number of indications including solid 
tumor and hematological malignancies, as either monotherapy or in combination with other 
chemotherapeutic agents. Like rapamycin, several newly approved rapalogs (temsirolimus and 
everolimus) are specific and allosteric inhibitors of mTORC1, and only partially inhibit mTORC1 
signaling pathways. They do not directly inhibit mTORC2, which has shown to be an emerging 


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target in cancer research. TAK-228 was developed to address the incomplete inhibition of the 
mTOR pathway by rapalogs by targeting both mTORC1 and mTORC2. 
 
In oncology, TAK-228 is being investigated as a treatment for advanced solid tumors and 
hematologic malignancies, either as monotherapy or in combination with chemotherapy, other 
molecularly targeted therapies, or anti-hormonal agents.  
 
1.2 
Nonclinical Summary 
 
1.2.1 Pharmacology 
TAK-228 selectively and potently inhibits mTOR kinase (the concentration inhibiting 50% of 
enzyme activity [IC50] is 1.1 nM), inhibits mTORC1/2 signaling, and prevents cellular 
proliferation. 
 
TAK-228 inhibited phosphorylation of downstream modulators of mTORC1 and mTORC2 in 
human U87 glioblastoma tumor xenograft models in mice and showed strong tumor growth 
inhibition (TGI) at tolerable oral (PO) doses in all 8 xenograft models tested (see IB Ed8 for 
details). 
 
1.2.2 Safety Pharmacology 
TAK-228 has a low potential to affect the human ether-à-go-go related gene (hERG) potassium 
ion channel and did not affect cardiovascular (CV) parameters in vivo in telemeterized monkeys. 
 
1.2.3 Drug Metabolism and Pharmacokinetics 
TAK-228 was rapidly absorbed after PO administration to mice, rats, dogs, and monkeys, with 
high oral bioavailability. [14C]TAK-228 was rapidly and widely distributed throughout the body in 
Long-Evans rats; radioactivity was eliminated from most tissues at 48 hours post-dose. TAK-228 
displayed dose-proportional plasma exposures, a moderate propensity to cross the blood-brain 
barrier, and was modestly bound (70.5%) to human plasma proteins. TAK-228 distributed mainly 
to the plasma of human blood. There was no obvious concentration-dependent red blood cell 
(RBC) distribution of TAK-228 in human blood. 
 
TAK-228 did not inhibit P-glycoprotein, but did inhibit breast cancer-resistance protein (BCRP), 
organic cation transporter (OCT)1 and OCT2. 
 
Recently completed in vitro metabolism experiments in human hepatocytes using 14C-labeled 
TAK-228 suggest that TAK-228 is metabolized primarily via CYP1A2 (approximately 31%-
40%), with a minor contribution from CYP3A4 (approximately 11%-22%). These data suggest 
that TAK-228 is also metabolized by direct glucuronidation (approximately 22%) and an 
unidentified non-uridine diphosphate glucuronosyl transferase pathway (approximately 18%). The 
new data differ from the previous in vitro CYP phenotyping data obtained using recombinant CYP 
enzymes, which suggested the involvement of CYP2C9 (approximately 35%), CYP2C19 
(approximately 28%), and CYP3A4 (approximately 28%) in TAK-228 metabolism. In addition, 
physiologically based PK modeling and simulation using the new metabolism data for TAK-228 
suggest that the risk for a metabolism-based drug-drug interaction with TAK-228 appears to be 
low. Therefore, strong CYP1A2 inhibitors and CYP inducers should be administered with caution 
and at the discretion of the investigator during the study.  


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1.2.4 Toxicology 
The toxicologic profiles obtained in the Good Laboratory Practice (GLP)-compliant and non-GLP-
compliant studies in rats and monkeys were generally consistent with pharmacologic inhibition of 
mTORC1/2 activity. Observed toxicities were mostly consistent between sexes. TAK-228 repeat-
dose GLP studies include completed 28-day and preliminary 3-month toxicology studies in rat and 
monkeys, and embryo-fetal studies in rats and rabbits. 
 
The primary dose-limiting toxicities (DLTs) of TAK-228 in rats and monkeys were secondary to 
an exaggerated pharmacologic response and consisted of body weight loss and associated clinical 
observations that included hunched posture, dehydration, gastrointestinal (GI) distress and 
decreased activity, appetite, and body temperature. In addition to the previously mentioned effects, 
a single monkey in the 3-month toxicology study demonstrated a DLT of skin toxicity 
characterized as progressive acanthosis. The highest exposures tolerated in the preliminary 3-
month rat and monkey toxicology studies were 1233 and 194 nghr/mL, respectively. 
 
Adverse effects in rats included body weight loss, decreased activity, increased glucose and 
insulin levels, alterations in white blood cells, bone marrow and lymphoid depletion, thymic 
necrosis, oligospermia, testes degeneration/atrophy, nonglandular stomach epithelial 
degeneration/ulceration/hyperplasia, pancreatic islet degeneration and fibrosis, lens fiber 
degeneration with cataract correlate, adrenal cortex hypertrophy, pituitary atrophy secondary to 
body weight loss, liver hepatocellular vacuolation, retinal dysplasia with or without optic nerve 
atrophy, and alveolar histiocytosis. The alveolar histiocytosis was only present in the 28-day rat 
study and was absent in the 3-month rat study. Both retinal dysplasia and alveolar histiocytosis are 
thought to be potential background findings. The pancreatic islet degeneration and fibrosis, as well 
as the other findings of lens fiber degeneration, pituitary atrophy, and liver vacuolation, were 
consistent with the mechanism of action (MOA) and effects observed with other rapalogs. The 
microscopic findings observed in the testes, epididymides, and eyes in the 28-day and/or 3-month 
rat studies were not resolved after a 14-day recovery period, while partial to complete resolution 
was seen in the pancreas, adrenal gland, pituitary, liver, lungs, thymus, nonglandular stomach, and 
bone marrow. 
 
The adverse effects in monkeys included hunched posture, dehydration, GI distress, and decreased 
activity, appetite, and body weight; increased glucose and insulin; lymphoid and bone marrow 
depletion; adrenal hypertrophy/hyperplasia; pancreatic and salivary gland acinar cell secretory 
depletion; neutrophilic inflammation of GI tract with occasional erosion and ulceration, skin 
effects including ulceration, epidermal hyperplasia, acanthosis and hyperkeratosis; and adipose 
tissue depletion. Additionally, there were sporadic inflammatory findings among some animals 
that were of uncertain association to the test article. The findings in the pancreas, adrenal glands, 
and salivary glands may have been related to a stress response or reduced food consumption. The 
findings observed in repeat-dose monkey studies were generally reversible after a 14-day recovery 
period. 
 
The findings in rat and monkey repeat-dose toxicology studies with TAK-228, including bone 
marrow and lymphoid depletion; GI, liver, pancreas, and skin effects; and effects on glucose and 
insulin levels, can be monitored in clinical trials. The toxicities seen in the repeat-dose toxicology 
studies, such as GI effects and glucose and insulin increases, are consistent with the treatment-


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emergent adverse events (TEAEs), including mucositis and hyperglycemia, observed to date in 
subjects receiving TAK-228. 
 
Rat and rabbit range-finding embryo-fetal studies demonstrated teratogenic, fetotoxic, and 
abortive effects with TAK-228. Embryo-fetal lethality and/or teratogenic effects have been 
reported with the mTORC1 inhibitors rapamycin and the rapalogs. 
 
TAK-228 was negative for genotoxicity in an in vitro bacterial mutagenesis (Ames) assay, an in 
vivo rat micronucleus assay, and an in vivo rat comet assay. An in vitro chromosomal aberration 
assay with TAK-228 in human peripheral blood lymphocytes (PBLs) was positive for 
chromosomal aberrations in the presence and absence of metabolic activation. However, the 
weight of evidence from the combined results of a negative mutagenicity assay and negative 
genotoxicity assessments in 2 in vivo assays in 3 tissues (bone marrow, liver, and duodenum) 
demonstrate that TAK-228 does not present a genotoxic risk. 
 
TAK-228 was negative for phototoxicity in the 3T3 fibroblast assay. 
 
1.3 
Clinical Experience with TAK-228 
 
TAK-228 is in clinical development as a single agent in 3 phase 1 studies including study 
INK128-00138 in subjects with advanced solid malignancies, study INK128-00239 in subjects with 
multiple myeloma [MM], non-Hodgkin lymphoma [NHL] and Waldenström macroglobulinemia 
[WM]) and study C31002 to measure the effect of TAK-228 on QTc interval in subjects with 
advanced solid malignancies.  It is also being investigated in combination with paclitaxel (with or 
without trastuzumab) in subjects 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 thus far include QD, QW, QD×3days per week (once daily for 
3 consecutive days followed by a 4-day dosing holiday every week), and QD×5days per week 
(once daily for 5 consecutive days followed by a 2-day dosing holiday every week). 
 
Please note that the data described in this section was obtained with the original unmilled TAK-
228 active pharmaceutical ingredient (API); the current manufacturing process produces milled 
TAK-228 API (see section 1.4). 
 
The table below summarizes TAK-228 doses, schedules, and active pharmaceutical ingredient 
(API) studied as well as evaluable PK population studies in all these studies. Details on PK and 
safety information for each study are available in the current IB edition. 


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Summary of TAK-228 Clinical Studies 
 
 
1.3.1 Pharmacokinetics 
Overall, pharmacokinetic (PK) data from Studies INK128-001, INK128-002, and INK128-003 
indicate that TAK-228 exhibits fast oral absorption (time to reach Cmax [tmax], generally between 
1-4 hours after dosing); has dose-linear PK, with a mean plasma half-life of approximately 
8 hours. TAK-228 does not accumulate meaningfully in plasma when dosed as frequently as once 
daily (QD) under any of 4 tested dosing regimens. The PK of TAK-228 was generally consistent 
across 3 phase I studies, suggesting no appreciable difference in the PK of TAK-228 among 
subjects with advanced solid tumors or subjects with MM or WM. 
 
There were no meaningful differences in the PK of TAK-228 when administered 24 hours after a 
30-minute IV infusion of 80 mg/m2 paclitaxel (Study INK128-003) compared with single-agent 
TAK-228 (Studies INK128-001 and INK128-002). The PK of paclitaxel also remained generally 
unaffected by TAK-228 co-administration, indicating the lack of a PK interaction between TAK-
228 and paclitaxel. 


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There were no readily apparent differences in either the Cmax or AUC of 4 mg TAK-228 unmilled 
or milled capsules when administered under fasted conditions. 
 
Compared to the fasted state, when 4 mg of milled TAK-228 API was administered following a 
standard high-fat breakfast, there was an approximately 38% reduction in Cmax and a delay in 
tmax (median tmax 6 hours [fed] vs. 2 hours [fasted]), but there was no meaningful change in 
AUC. The differences observed when TAK-228 was dosed under fed versus fasted conditions may 
help explain the different MTDs determined for TAK-228 QD dosing in Study INK128-001 
compared with study MLN0128-1004. 
 
There were no readily apparent differences in the PK of TAK-228 when administered in 
conjunction with either 25 mg exemestane or with 500 mg fulvestrant. 
 
1.3.2 Safety 
As of the clinical data cutoff (09 December 2015), a total of 438 subjects had received ≥ 1 dose of 
study drug across studies. A total of 20 deaths occurred within 30 days of the last study drug dose. 
Of these fatal events, 1 death (ventricular fibrillation and cardiac arrest; Study INK128-001) was 
considered related to TAK-228. 
 
Across the studies and regardless of causality or dosing regimen, the most common TEAEs 
included nausea, fatigue, hyperglycemia, vomiting, diarrhea, stomatitis, and decreased appetite. 
 
1.4 
Updated Manufacturing Process 
A new TAK-228 capsule containing milled active pharmaceutical ingredient (API) is available for 
new clinical studies in 1 mg, 3 mg and 5 mg strengths.  
 
The milled API, may result in faster absorption profile with possibly higher maximum 
concentration (Cmax), which could result in a different safety profile compared to the previous 
unmilled API capsules. Therefore, ongoing studies (C31001, C31002 and MLN0128-1004 [A 
Phase I, open label study to evaluate the safety, tolerability, and pharmacokinetics of TAK-228 
as a single agent and in combination with paclitaxel in adult subjects with advanced non-
hematological malignancies]), with the new milled API will determine the recommended phase 
2 dose (RP2D) for single agent 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. 
 
1.5 
Clinical Summary of Safety 
 
1.5.1 Special Warnings and Precautions for Use 
 
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 


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blood glucose ≥ 150 mg/dL measured by glucometer would initiate closer monitoring of serum 
glucose and possible intervention. Subjects with Grade 1 hyperglycemia (fasting serum glucose 
[FSG] > the upper limit of the normal range ≤ 160 mg/dL) are treated with oral hypoglycemic 
agents (eg, metformin), and subjects with ≥ Grade 2 hyperglycemia (FSG > 160 mg/dL) are 
treated aggressively with oral hypoglycemic agents and/or insulin as clinically indicated. Daily 
home monitoring and early treatment have resulted in good control of glucose levels for the 
majority of TAK-228-treated subjects who developed hyperglycemia.  
 
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 1 report of ventricular fibrillation and cardiac arrest post dose that had a fatal outcome and 
was assessed as related to TAK-228. Routine cardiac monitoring with baseline and on-study 
electrocardiograms (ECGs) and physical examination constitute the core cardiac safety monitoring 
in all TAK-228 studies. 
 
Preliminary results from a dedicated study of the effects of TAK-228 on the QTc interval (study 
C31002) show lack of clinically relevant effects on QTc interval, PR and QRS intervals, minimal 
effects on heart rate, and absence of treatment-emergent ECG morphology findings and therefore 
the treatment with TAK-228 is not associated with clinically meaningful effects on the overall 
electrocardiographic safety profile (further details available in 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. 
 
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. Subjects should be encouraged to drink at 
least 20 ounces of fluids a day, especially on days requiring fasting (per protocol), with 
administration of IV fluids in the clinic as indicated to avoid dehydration. 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, to further evaluate possible 
etiologies for the renal dysfunction. 
 
Rash 
Rash observed in clinical studies of TAK-228 tends to be maculopapular and pruritic and has 
ranged from Grade 1 to 3. For the most part, rash and pruritus improve with antihistamines, topical 


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steroid creams, and/or dose interruption. Some subjects have required pulse systemic steroids, 
dose reduction, and/or study treatment discontinuation. 
 
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. 
 
1.5.2 Interactions With Other Medicaments and Other Forms of Interaction 
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. 
 
See also Section 10.1.8, Special Warnings and Special Precautions for Use.  
 
1.6 
Study Rationale 
 
The mTOR pathway is an important target implicated in HCC pathogenesis. Although mTORC1 
inhibitors have not demonstrated efficacy in the second line post sorafenib failure, two important 
confounders include the requirement for prior sorafenib exposure with resultant poor prognosis 
study group, and the upregulation/activation of the Akt pathway resulting from everolimus 
mTORC1 inhibition. TAK-228 is a novel dual mTORC1 and mTORC2 inhibitor with encouraging 
signals of clinical activity in phase I HCC trials.  
 
Accordingly, we propose an open label, randomized phase I/II study of TAK-228 versus sorafenib, 
the current standard of care.  
 
The primary endpoint of the phase I study will be to determine the maximum tolerated dose 
(MTD) of the milled API capsules of TAK-228.  Three dose levels will be evaluated.  
 
The primary endpoint of the phase II study will be time to progression rather than progression-free 
survival, as in the HCC population death due to non-cancer related underlying liver disease (e.g. 
cirrhosis) is not uncommon. 
 
Although the primary goal of the phase II clinical trial is to evaluate time to progression, this study 
is important because other correlatives will provide critical information. In addition to 
characterizing pharmacokinetics, we plan to assess diagnostic tissue for evaluation of 
phosphorylated Akt, mTOR, 4EBP1, and S6 kinase40, and correlate this with subject outcomes. 
Additionally, we plan to characterize oncogene expression affecting mTOR activation via targeted 
deep sequencing assay designed to interrogate the coding exons of approximately 200 genes 
commonly mutated in human cancers41.  
 


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2 
OBJECTIVES AND ENDPOINTS 
 
2.1 
Phase I Objectives 
 
2.1.1 Primary Objective 
The primary objective of this prospective, open label dose escalation study is to establish 
the maximum tolerated dose of TAK-228 in the first line setting of advanced 
hepatocellular carcinoma (HCC). 
 
2.1.2 Secondary Objectives 
 
Characterize adverse effects (AE) 
 
Measure overall survival (OS) 
 
Evaluate time to progression (TTP) 
 
Measure progression-free survival (PFS) 
 
Determine objective response rate (ORR) and disease control rate (DCR) at 16 and 
24 weeks 
 
2.2 
Phase II Study Objectives 
 
2.2.1 Primary Objective 
The primary objective of this prospective, open label, randomized study is to evaluate time 
to progression (TTP) associated with TAK-228 in the first line setting of advanced 
hepatocellular carcinoma (HCC), compared to a control arm treated with sorafenib. 
 
2.2.2 Secondary Objectives 
 Measure overall survival (OS) 
 Measure progression free survival (PFS) 
 Characterize adverse effects (AE) 
 Determine radiographic response via objective response rate (ORR) and disease control 
rate (DCR) at 16 and 24 weeks 
 
2.2.3 Correlative Objectives  
 Assess pharmacokinetics (PK) of TAK-228 
 Evaluate mTOR and PI3K/Akt expression and phosphoproteins via 
immunohistochemistry (IHC) 
 Characterize oncogene expression affecting mTOR activation via targeted deep 
sequencing assay 
 Assess tumor necrosis and modified RECIST (mRECIST) criteria 
 


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2.3 
Phase I Study Endpoints 
 
2.3.1 Primary Endpoint 
The primary endpoint is determination of the maximum tolerated dose of TAK-228. MTD 
is defined as the dose level at which fewer than 33% of subjects experience a dose limiting 
toxicity (DLT). 
 
2.3.2 Secondary Endpoints 
 Adverse effects (AE) as defined by CTCAE v4 
 Overall survival (OS) as defined by the time from randomization to date of death from 
any cause. 
 Time to progression (TTP) as defined as the time from randomization until tumor 
progression as defined by RECIST v1.1. 
 Progression free survival (PFS) as defined by time from randomization to tumor 
progression or death from any cause. 
 Objective response rate (ORR) as defined as complete response (CR) + partial response 
(PR), and disease control rate (DCR) as defined by RECIST v1.1, as a sum of stable 
disease (SD for 8 weeks), partial response (PR), and complete response (CR) 
 
2.4 
Phase II Study Endpoints 
 
2.4.1 Primary Endpoint 
The primary endpoint is determination of the time to progression (TTP), which is defined as 
the time from randomization until tumor progression as defined by RECIST v1.1. 
 
2.4.2 Secondary Endpoints 
 Overall survival (OS) as defined by the time from randomization to date of death from 
any cause. 
 Progression free survival (PFS) as defined by time from randomization to tumor 
progression or death from any cause 
 Adverse effects (AE) as defined by CTCAE v4 
 Objective response rate (ORR) as defined as complete response (CR) + partial response 
(PR), and disease control rate (DCR) as defined by RECIST v1.1, as a sum of stable 
disease (SD for 8 weeks), partial response (PR), and complete response (CR) 
 
2.4.3 Correlative Endpoints 
 Assess Pharmacokinetics (PK) in first 10 subjects in TAK-228 arm 
 Evaluate mTOR and PI3K/Akt expression and phosphoproteins via 
immunohistochemistry (IHC) of phosphorylated Akt, 4EBP1, S6 kinase, and ERK1/2 
 Characterize oncogene expression affecting mTOR activation via targeted deep 
sequencing assay designed to interrogate genes commonly mutated in human cancers. 
 Assess tumor necrosis and modified RECIST (mRECIST) criteria.  
 


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3 
ELIGIBILITY CRITERIA 
 
3.1 
Inclusion Criteria 
 
Each subject must meet all of the following inclusion criteria to be enrolled in the study: 
 
3.1.1 Male or female subjects 18 years or older at the time of informed consent.  
3.1.2 Voluntary written consent must be signed before performance of any study related 
procedure not part of standard medical care, with the understanding that the subject may 
withdraw consent at any time without prejudice to future medical care. 
3.1.3 Females of childbearing potential must agree to practice 2 effective methods of 
contraception, at the same time, from the time of signing the informed consent through 90 
days after the last dose of study drug, or agree to completely abstain from heterosexual 
intercourse. 
3.1.4 Females of childbearing potential must have a negative serum pregnancy test within 7 days 
prior to prior to registration for protocol therapy. 
NOTE:  Female subjects are considered of childbearing potential unless they are surgically 
sterile (they have undergone a hysterectomy, bilateral tubal ligation, or bilateral 
oophorectomy) or they are naturally postmenopausal for at least 12 consecutive months. 
 
3.1.5 Male subjects, even if surgically sterilized (i.e., status post-vasectomy), must agree to 
practice effective barrier contraception during the entire study treatment period and 
through 120 days after the last dose of study drug, or agree to completely abstain from 
heterosexual intercourse. 
3.1.6 Subjects must have a diagnosis of measurable advanced or metastatic hepatocellular 
carcinoma. Advanced HCC is defined as disease not amenable to surgery, ablation, 
transplant, or embolic therapy.  
3.1.7 Phase II subjects must be willing to provide a tissue biopsy prior to registration if archived 
HCC tumor tissue is not available for correlative studies. 
3.1.8 For the phase I cohort, subjects will have no restrictions on the number of prior systemic 
therapies; phase I patients may also be treatment naïve.  
3.1.9 Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2. 
3.1.10 Adequate organ function, as specified below, within 28 days before study registration:  
3.1.10.1 Bone marrow reserve consistent with: absolute neutrophil count (ANC) ≥ 1.5 x 
109/L; platelet count ≥ 50 x 109/L; hemoglobin ≥ 9 g/dL; 
3.1.10.2 Hepatic: total bilirubin ≤ 2 x upper limit of normal (ULN), transaminases (aspartate 
aminotransferase/serum glutamic oxaloacetic transaminase-AST/SGOT and alanine 
aminotransferase/serum glutamic pyruvic transaminase-ALT/SGPT) ≤ 5 x ULN  
3.1.10.3 Renal: creatinine clearance ≥50 mL/min based either on Cockcroft-Gault estimate 
or based on urine collection (12 or 24 hour); 
3.1.10.4 Metabolic: Glycosylated hemoglobin (HbA1c) ≤7.0%, fasting serum glucose (≤ 
130 mg/dL) and fasting triglycerides ≤ 300 mg/dL.  


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NOTE: Subjects with a history of transient glucose intolerance due to corticosteroid 
administration are allowed in this study if all other inclusion/exclusion criteria are 
met. 
3.1.11 Ability to swallow oral medications. 
3.1.12 Measurable disease according to RECIST v1.1 and obtained by imaging within 28 days 
prior to registration for protocol therapy.   
NOTE: A subject with prior brain metastasis may be considered if they comply with 
inclusion criteria 3.1.13 below.  
3.1.13 Subjects who have a history of brain metastasis are eligible for the study provided all the 
following criteria are met: 
3.1.13.1 Must have completed their treatment for brain metastasis 
3.1.13.2 Must be asymptomatic 
3.1.13.3 Must not have evidence of disease progression for ≥3 months or hemorrhage after 
treatment;  
3.1.13.4 Must be off-treatment from dexamethasone for 4 weeks prior to study registration 
and  
3.1.13.5 Must not have an ongoing requirement for dexamethasone or anti-epileptic drugs. 
3.1.14 Prior locoregional liver directed therapy is allowed as long as treatment was at least 6 
weeks prior to study registration, and clear progression is demonstrated by RECIST v1.1 
criteria. Subject must have recovered from the acute toxic effects (≤ grade 1 CTCAE v4) of 
previous anti-cancer treatment prior to study enrollment; the only exception is that grade 2 
neuropathy is permitted. 
3.1.15 Prior radiation therapy is allowed to < 25% of the bone marrow, but is not permitted within 
28 days prior to study registration.  
3.1.16 Estimated life expectancy ≥ 3 months as determined by the treating physician. 
 
3.2 
Exclusion Criteria 
 
Subjects meeting any of the following exclusion criteria are not to be enrolled in the study: 
 
3.2.1 Female subjects who are both lactating and breastfeeding 
3.2.2 Any serious medical or psychiatric illness that could, in the investigator’s opinion, 
potentially interfere with the completion of treatment according to this protocol. 
3.2.3 Treatment with any investigational products within 28 days prior to study registration. 
3.2.4 No prior systemic treatment is allowed for subjects in the phase II cohort. 
3.2.5 Failed to recover from the reversible effects of prior anticancer therapies with the 
exception of alopecia and grade 2 neuropathy. 
3.2.6 Have initiated treatment with bisphosphonates less than 30 days prior to study registration. 
Concurrent bisphosphonate use is only allowed if the bisphosphonate was initiated at least 
30 days prior to study registration.  


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3.2.7 Manifestations of malabsorption due to prior gastrointestinal (GI) surgery, GI disease, or 
for an unknown reason that may alter the absorption of TAK-228. 
3.2.8 No condition that could affect the absorption of study drug, including any of the following: 
 Malabsorption syndrome 
 Disease significantly affecting gastrointestinal function 
 Bowel obstruction or sub-obstruction 
3.2.9 History of any of the following within the last 6 months prior to study registration: 
3.2.9.1 
Ischemic myocardial event, including angina requiring therapy and artery 
revascularization procedures 
3.2.9.2 
Ischemic cerebrovascular event, including TIA and artery revascularization 
procedures 
3.2.9.3 
Requirement for inotropic support (excluding digoxin) or serious (uncontrolled) 
cardiac arrhythmia (including atrial flutter/fibrillation, ventricular fibrillation or 
ventricular tachycardia)  
3.2.9.4 
Placement of a pacemaker for control of rhythm 
3.2.9.5 
New York Heart Association (NYHA) Class III or IV heart failure (See Study 
Procedures Manual) 
3.2.9.6 
Pulmonary embolism  
3.2.10 Significant active cardiovascular or pulmonary disease at the time of study registration, 
including: 
3.2.10.1 Uncontrolled high blood pressure (i.e., systolic blood pressure >160 mm Hg, 
diastolic blood pressure > 95 mm Hg) 
3.2.10.2 Pulmonary hypertension 
3.2.10.3 Uncontrolled asthma or O2 saturation < 90% by ABG (Arterial Blood Gas) 
analysis or pulse oximetry on room air 
3.2.10.4 Significant valvular disease; severe regurgitation or stenosis by imaging 
independent of symptom control with medical intervention, or history of valve 
replacement 
3.2.10.5 Medically significant (symptomatic) bradycardia 
3.2.10.6 History of arrhythmia requiring an implantable cardiac defibrillator 
3.2.10.7 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)  
3.2.11 Initiation of treatment with hematopoietic growth factors, transfusions of blood and blood 
products, or systemic corticosteroids (either IV or oral steroids, excluding inhalers) within 
1 week prior to study registration (subjects already receiving erythropoietin on a chronic 
basis for ≥ 28 days are eligible). 
3.2.12 Other clinically significant co-morbidities, such as uncontrolled pulmonary disease, active 
central nervous system disease, active infection, or any other condition that could 
compromise participation of the subject in the study. 
3.2.13 Cirrhosis with Child-Pugh score > 7 (see Study Procedures Manual) 


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3.2.14 Variceal bleeding within 1 month prior to study registration. 
3.2.15 Refractory encephalopathy or ascites 
3.2.16 Known HIV positivity 
3.2.17 Hepatitis B surface antigen (HBsAg) positivity without active treatment. A subject found 
to be HBsAg positive should be on antiviral therapy for at least two weeks prior to study 
registration. 
3.2.18 Subjects who are taking proton pump inhibitors (PPIs) within 7 days of study registration 
or who require treatment with PPIs throughout the trial or those who are taking H2 
receptor antagonists within 24 hours of study registration.  
 
4 
SUBJECT REGISTRATION  
 
All subjects must be registered and randomized through BTCRC Administrative Headquarters’ 
electronic data capture (EDC) system. 
 
Subjects must be registered and randomized prior to starting protocol therapy. Subjects must be 
randomized within 1 business day of registration and should begin therapy within 5-10 business 
days of randomization. Beginning therapy outside that timeframe will not be considered a deviation. 
 
Detailed guidelines for subject registration and randomization can be found in the electronic case 
report form (eCRF) guidelines associated with this protocol.  
 
Blinding 
The study treatment is not blinded to the subject or the investigator. 
 
 
5 
STUDY DESIGN AND TREATMENT PLAN 
 
5.1 
Overview of Study Design 
This is an open label, multi-center, randomized phase I/II study of TAK-228 versus standard 
sorafenib.  
 
5.2 
Number of Subjects 
Phase I: Up to 18 subjects will be registered. 
 
Phase II: The total number of subjects to be registered and randomized is 100. 
 
5.3 
Duration of Study 
Study duration will be from time of registration until treatment cessation, due to progression, 
death, or withdrawal for any reason. 
 
Study cycles are defined as a period of 28 days.  
 


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5.4 
Phase I Dose Escalation Study 
 
5.4.1 Phase I Treatment Plan 
All Phase I subjects will receive TAK-228. TAK-228 will be administered orally on days 1, 8, 15 
and 22 in successive cohorts. The escalation phase will follow a standard “3+3” design. Subjects 
will be accrued to each dose level in cohorts of up to 3-6 evaluable subjects. Escalation will 
continue until 2 DLT are observed in a cohort, or until the highest planned dose level is reached. 
 
After informed consent and study registration, subjects will receive protocol therapy according to 
the table below.  
 
Dose 
Cohort 
# of Subjects 
TAK-228 
TAK-228 capsules: 
Number and Strength 
1 (start) 
3-6 
15mg QW 
Three 5-mg capsules 
2 
3-6 
20mg QW 
Four 5-mg capsules 
3 
3-6 
30mg QW 
Six 5-mg capsules 
 
5.4.2 Phase I Maximum Tolerated Dose (MTD) and Dose Escalation Rules: 
To define the Maximum Tolerated Dose (MTD), subjects will be evaluated for DLT in the first 28 
days of treatment (1 cycle).  
 
Note: A withdrawal or death within the first 4 weeks not related to treatment will not be 
considered a DLT. 
 
The MTD is defined as the dose level at which fewer than 33% of subjects experience a dose 
limiting toxicity (DLT), and specifically is the dose level at which less than 2 out of 6 subjects 
experience DLT. The MTD will be the recommended dose for the Phase II component of the 
study. 
 
Subjects will initially be enrolled onto dose level 1. Three to six evaluable subjects will be 
enrolled at each dose level. All subjects assigned to a dose level must be followed for at least 4 
weeks before dose escalation to the next cohort level can begin. 
 
Note: Subjects not evaluable for DLT assessment (i.e. do not complete at least 1 cycle of therapy 
due to reasons other than toxicity) on the Phase I portion of the protocol will be replaced for 
determination of dose escalation. 
 
The following rules will be followed: 
 
 An initial three subjects will be enrolled at dose level +1. If all 3 subjects in dose level +1 
complete 4 weeks of therapy without dose limiting toxicity (DLT), the study will proceed to 
enroll 3 subjects at dose level +2. If all 3 subjects in dose level +2 complete 4 weeks of 
therapy without DLT, the study will proceed to enroll 3 subjects at dose level +3. If all 3 
subjects in dose level +3 complete 4 weeks of therapy without DLT, 3 more subjects will be 
enrolled to ensure that only 0-1 of 6 subjects have a DLT and then proceed to the Phase II 


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cohort. As dose level +3 represents the full dose of TAK-228, there will be no further dose 
escalation beyond dose level +3. 
 
 Alternatively, if 1 of the first 3 subjects in any given dose cohort experiences DLT, an 
additional 3 subjects will be enrolled at that dose level. If only 1 of the total 6 subjects in a 
dose level experience DLT, the study will proceed to the next dose level as planned. If 2 of the 
total 6 subjects in any given dose cohort experience DLT, the next lower dose level will be 
explored and considered the maximum tolerated dose (MTD) if no more than 1 of 6 subjects 
experience a DLT. That dose will be recommended for the Phase II study. 
 
 If 2 or more DLTs are reached in dose level +1, the study will be put on hold and a protocol 
amendment will be considered. 
 
 
Dose Escalation Rules 
 
Number of subjects with 
DLT at given dose level 
Escalation decision 
0 out of 3 
Enter 3 subjects at the next dose level. 
≥2 out of 3 
Dose escalation will be stopped. This dose level will be declared 
the maximum administered dose. Three (3) additional subjects 
will be entered at the next lowest dose level if only 3 subjects 
were treated previously at that next lowest dose level. 
1 out of 3 
Enter at least 3 more subjects at this dose level: 
 If 0 of these additional 3 subjects experience DLT, proceed to 
the next dose level. 
 If 1 or more of these additional 3 subjects experience DLT, 
then dose escalation is stopped and this dose is declared the 
maximum administered dose. Three (3) additional subjects 
will be entered at the next lowest dose level if only 3 subjects 
were treated previously at that dose. 
≤1 out of 6 at highest dose 
level below the maximum 
administered dose 
This will be defined as the MTD. This dose level will be the 
recommended Phase II dose.  
 
 
 


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5.4.3 Phase I Dose-Limiting Toxicities (DLTs): 
 
The National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) 
version 4 (http://ctep.cancer.gov) will be used to characterize toxicities.  
 
DLT is defined as an adverse event related (possible, probable or definite) to study treatment 
occurring during the first cycle of therapy and fulfilling one of the following criteria: 
 
 ≥ grade 4 hematologic toxicity or ≥ grade 3 non hematologic toxicity (excluding transaminitis 
< 10x ULN lasting less than one week, nausea or emesis or diarrhea of no longer than 48 hours 
duration without medical intervention). Grade 4 vomiting or diarrhea is considered DLT.  
 Delay of Cycle 2 for greater than 2 weeks due to drug-related toxicities 
 Grade 3 or 4 febrile neutropenia regardless of duration 
 Grade 3 thrombocytopenia with clinically significant bleeding (assessed with standard of care 
labs) 
 Grade 4 thrombocytopenia regardless of duration.  
 
DLTs will be counted based on the number of subjects with DLT at a given dose level, not the 
absolute number of DLTs. No single subject can trigger more than one DLT event.  
 
Additional subject cohorts will not be enrolled at the next dosing level until all subjects at the current 
dosing level complete all planned treatment for cycle 1 (defined as 4 doses of TAK-228) and are 
able to start cycle 2 with no more than a 2-week delay. 
 
Intra-subject dose escalation is not permitted. 
 
Once the maximum tolerated dose of TAK-228 is determined, enrollment will continue until at least 
6 subjects total are accrued at the maximum tolerated dose. 
 
5.5 
Phase II Study 
 
5.5.1 Phase II Stratification Factors and Randomization Process Prior to Initiating Study 
Treatment 
 
Randomization will take place following completion of the screening evaluations and eligibility 
assessments. Stratification factors will be employed during randomization to minimize between-
arm assignment imbalance. 
1 Child-Pugh score 5-6 
2 Child-Pugh score 7 
 
Within the strata, subjects will be randomly assigned with equal probability to either the 
investigational arm (Arm A: TAK-228) or the control arm (Arm B: sorafenib). 
 
5.5.2 Phase II Treatment Plan 
 
Subjects will be randomized to receive either TAK-228 or sorafenib.  
 


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5.5.1 Arm A: MLN 0128 will be administered orally at the recommended phase II dose (RP2D) 
once weekly. Dose modification will be allowed for grade 3 or higher toxicities, or 
intolerable grade 2 toxicities.  
 
5.5.2 Arm B: Sorafenib will be administered at 400mg PO BID daily, with dose adjustment per 
standard of care.   
 
5.5.3 Study evaluations will include medical histories that will capture information about drug 
toxicity and performance status. Subjects will undergo routine physical examinations, 
including vital signs; height, weight, and measurement for body surface area. Laboratory 
measurements will be obtained throughout the study as needed. Tissue samples will be 
evaluated for mTOR and PI3K/Akt pathway proteins and phosphoproteins by IHC 
expression. A schedule of activities is presented in the study calendar. To complete this trial 
in a timely manner, the primary end point is time to progression.   
 
 
Drug 
Dose 
Route of 
administration Length of cycle
Arm A 
TAK-228 
RP2D once 
weekly 
oral 
28 days 
Arm B 
Sorafenib 
400mg BID 
daily
oral 
 
5.6 
Criteria for administration of subsequent treatment cycles 
A new treatment cycle will only be initiated when all of the following conditions are met: 
 ANC ≥ 1.5 x 109/L 
 Platelets ≥ 50 x 109/L 
 Non-hematologic treatment related toxicities have improved to grade 1 or resolved 
(CTCAE v. 4) 
Institution standards should be followed for hydration and symptom management.  
 
5.7 
Pre-medication  
None is required, but can be utilized per clinician discretion. 
5.8 
Drug Administration 
 
5.8.1 TAK-228 Administration 
TAK-228 will be administered once weekly at approximately the same time each day. It is 
recommended that each dose of TAK-228 be given orally with 8 ounces (240 mL) of water. TAK-
228 should be administered on an empty stomach. Subjects 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.  
 
Subjects should be instructed to take their study medication at approximately the same time on 
each scheduled dosing day and not to take more than the prescribed dose at any time. Subjects 
should swallow the study medication whole and not chew it, open it, or manipulate it in any way 


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before swallowing. If a subjects does not take their TAK-228 dose within 24 hours of the QW 
scheduled dosing time, the dose should be skipped and considered a missed dose. Subjects should 
record any missed doses in their diary and resume drug administration at the next scheduled time 
with the prescribed dosage. Under no circumstance should a subjects repeat a dose or double-up 
doses. 
 
TAK-228 will be administered only to eligible subjects under the supervision of the investigator or 
identified sub-investigator(s) during Cycle 1 for all TAK-228 subjects and during Cycle 2 Day 1 
for the first 10 subjects randomized to Phase II arm A; subsequent doses may be taken at home.  
 
Cycles are repeated every 28 days. 
 
5.8.2 TAK-228 Missed doses:  
If severe emesis or mucositis prevents the subject from taking an TAK-228 dose, that dose will be 
skipped. If emesis occurs after study medication ingestion and whole capsule(s) are visible in the 
vomitus, replacement capsule(s) should be taken; otherwise, the dose will not be re-administered, 
and subjects should simply adhere to the dosing schedule and resume dosing at the next scheduled 
time with the prescribed dosage. Subjects should record the time of the emesis in their dosing 
diary (see the Study Procedures Manual). Under no circumstance should a subject repeat a dose or 
double-up doses. 
 
5.8.3 Sorafenib Administration:   
Sorafenib should be administered on an empty stomach, 1 hour before or 2 hours after eating. It is 
recommended that each dose of sorafenib be given orally with 8 ounces (240 mL) of water. 
Sorafenib may be taken at home from the start. 
 
Cycles are repeated every 28 days.  
 
5.8.4 Sorafenib Missed Doses:  
Missed doses can be taken up to 4 hours of the time that the dose was scheduled. If the timing is 
beyond 4 hours, the subject will skip the dose and take the next dose as scheduled. Under no 
circumstances should a subject double-up doses.  
 
5.9 
Supportive Care 
TAK-228 and sorafenib are associated with adverse effects. The following medications may be 
given to subjects depending on the side effects they report: acetaminophen for fevers, meperidine 
for chills, anti-emetics for nausea and vomiting.  
 
There is no restriction on use of topical medications/lotions for prevention of hand-foot syndrome 
caused by sorafenib. 
 
5.10 
Excluded Concomitant Medications and Procedures 
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 


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study for pre-existing lesions) 
 Systemic corticosteroids (either IV or oral steroids, excluding inhalers), unless necessary for 
treatment of TAK-228 related AE, ie, rash (pre-medication for paclitaxel combo) 
 Anti-epileptic drugs for subjects with treated brain metastasis 
 Concomitant administration of any proton pump inhibitor (PPI) is not permitted during the 
study. Subjects 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. 
 
5.11 
Permitted Concomitant Medications and Procedures 
 
Prophylactic use of anti-emetic, anti-nausea, and antidiarrheal medications is encouraged and may 
be used prior to first dose of TAK-228 or sorafenib and as needed throughout the study prior to 
each dosing and as clinically indicated per standard practice. When selecting an anti-emetic agent, 
drugs that do not have an effect on the QT interval, such as palonosetron, are preferred. 
 
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. Subjects 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 and nizatidine. Cimetidine, a 
moderate cytochrome P450 (CYP)1A2 inhibitor, is not recommended as a first choice H2 receptor 
antagonist.  
 
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 administration days. However, for all other cycles in the 
phase 1b portion of the study and throughout the phase 2 portion of the study, administration of 
neutralizing antacids and calcium preparations is permitted except from 2 hours before until 2 
hours after TAK-228 administration. Some anti-gas preparations may also have antacid properties, 
and should also not be permitted from 2 hours before until 2 hours after study drug administration. 
 
Strong CYP1A2 and CYP inducers should be administered with caution, at the discretion of the 
investigator (see SPM). Alternative treatments, if available, should be considered. 
 
Moderate CYP1A2 inhibitors: cimetidine, methoxsalen 
 
Strong CYP1A2 inhibitors: fluvoxamine, ciprofloxacin 
 
Clinically significant enzyme inducers: rifampin, rifapentine, rifabutin, phenytoin, 
carbamazepine, phenobarbital, St. John’s Wort. 
 
Other medications considered necessary for the safety and wellbeing of the subjects may be 
administered at the discretion of the investigator. 
 
 
 


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5.12 
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, yellow fever, varicella, and TY21a 
typhoid vaccines. 
 
No dietary restrictions will be imposed on study subjects other than daily fasting for glucose 
monitoring. 
 
Subjects who show evidence of hyperglycemia during the study should be encouraged to follow a 
low carbohydrate diet.  
 
Pregnancy 
It is not known what effects TAK-228 has on human pregnancy or development of the embryo or 
fetus. Therefore, female subjects participating in this study should avoid becoming pregnant, and 
male subjects should avoid impregnating a female partner. Non-sterilized female subjects of 
reproductive age group and male subjects should use effective methods of contraception through 
defined periods during and after study treatment as specified below. 
 
Female subjects must meet 1 of the following:  
 Postmenopausal for at least 1 year before the screening visit, or 
 Surgically sterile, or 
 If they are of childbearing potential, agree to practice 2 effective methods of contraception 
from the time of signing of the informed consent form through 90 days (3 months) after the 
last dose of study drug, or agree to completely abstain from heterosexual intercourse. 
 
Male subjects, even if surgically sterilized (i.e., status post-vasectomy) must agree to 1 of the 
following: 
 Practice effective barrier contraception during the entire study treatment period and 
through 120 days (4 months) after the last dose of study drug, or completely abstain from 
heterosexual intercourse. 
 
6 
DOSE MODIFICATIONS  
 
The NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 4 will be used to 
grade adverse events. 
 
Subjects enrolled in this study will be evaluated clinically and with standard laboratory tests 
before and at regular intervals during their participation in this study as specified in Section 7. 
 
Subjects will be evaluated for adverse events (all grades), serious adverse events, and adverse 
events requiring protocol therapy interruption or discontinuation at each study visit for the 
duration of their participation in the study.  
Subjects discontinued from the treatment phase of the study for any reason will be evaluated at 
least 30 days (± 7) after the last dose of protocol therapy. 


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Phase I component: 
Dose modifications of TAK-228 during Cycle 1 of treatment in the Phase I component of the 
study will follow criteria specified (Section 5.4.3) and will be considered DLT (inability to deliver 
TAK-228 at the intended dose level). 
 
In second and subsequent cycles, the guidelines outlined for dose adjustments for the Phase II 
component of the protocol should be followed. 
 
Phase II component: 
Subjects will be monitored for toxicity. Appropriate adjustment of dose, delay or discontinuation 
of drugs will be made as outlined below for each drug. 
 
6.1 
Treatment-Limiting Adverse Events 
 
A treatment-limiting adverse event is any adverse event related to protocol therapy experienced 
during the study resulting in treatment termination.  
 
6.2 
TAK-228 Dose Modifications 
 
TAK-228 dosing should be withheld for ≥ Grade 2 renal insufficiency or ≥ Grade 3 TAK-228-
related toxicities. If the event resolves to Grade ≤ 1 or baseline values within 28 days of 
interrupting therapy, the subject may resume study treatment at a dose reduction.  
See table of dose adjustments below according to the schedule applied in this protocol.  
 
If TAK-228 dosing is delayed for > 28 consecutive days for TAK-228-related toxicity despite 
supportive treatment per standard clinical practice or more than 2 dose reductions of TAK-228 is 
required in a subject, stop TAK-228 therapy, discontinue the subject from the study drug 
administration, and complete the follow-up visit within 30 days of the last administration of TAK-
228. 
 
See Section 6.4 for management of TAK-228 dosing for specific clinical events. 
 
Table of Dose Adjustments for TAK-228 dosing on a weekly (QW) schedule 
Dose Level* 
Dose 
TAK-228 capsules: Number 
and Strength 
1 
30 mg
Six 5-mg capsules
-1 
20 mg 
Four 5-mg capsules 
-2 
15 mg
Three 5-mg capsules
-3 
10 mg
Two 5-mg capsules
-4 
Discontinue
 
*Level 1 represents the RP2D dose. If the RP2D is found to be 20mg, level -1 will be 15mg 
and level -2 will be 10mg.  Likewise, if the RP2D is found to be 15mg, level -1 dose will be 
10mg and level -2 will be to discontinue and protocol amendment will be submitted. 
 


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6.3 
Management of TAK-228 Clinical Events  
 
6.3.1 Management of Hyperglycemia 
 
In addition to obtaining fasting serum glucose (FSG) levels at clinic visits, all subjects 
receiving TAK-228 will be given a glucometer to monitor their daily fasting blood glucose 
(FBG) levels at home.  The level should be collected daily, pre-dose on dosing days, and at 
approximately the same time each day. 
 
All subjects receiving TAK-228 will be provided an in-home glucometer. Subjects will be 
trained on proper use of the glucometer and instructed to collect a daily FBG level every 
morning (predose on dosing days). Subjects will be instructed to bring the glucometer with 
them to each study visit so that the data collected can be reviewed and recorded in the 
source documents. Site investigators will be responsible for reviewing the home glucose 
monitoring logs for hyperglycemia. 
 
Subjects will be instructed to notify the site staff immediately with any abnormal readings 
(ie, ≥ 150 mg/dL) for further instructions on the management of their hyperglycemia.  
Hyperglycemia observed during home glucose monitoring should be confirmed in the 
clinic.  If no irregularities in the fasting blood glucose level are observed during a 
minimum of 2 consecutive months, the frequency of in-home fasting blood glucose testing 
may be reduced to a minimum frequency of once weekly if the investigator approves.  
Subjects will continue to notify the investigator of fasting blood glucose levels that exceed 
150 mg/dL and, if blood glucose levels are not well-controlled, or if the subject requires 
either oral hypoglycemic agents or insulin to control blood glucose levels, the frequency of 
in-home testing of fasting blood glucose levels will be reinstated to daily. 
 
In the event that any FSG reading performed at the site indicates hyperglycemia (> upper 
limit of normal [ULN] or ≥ 110 mg/dL), the study staff should first ascertain that the 
subject was fasting at the time of the blood draw (ie, nothing by mouth for at least 8 hours 
prior to blood being obtained), had continued to take their concomitant antiglycemic 
medications should the subject have underlying diabetes mellitus, and repeat the FSG as 
needed.  If the repeat FSG continues to demonstrate hyperglycemia, investigators should 
initiate steps to aggressively manage the hyperglycemia per standard clinical practice.  The 
following guidelines are provided to aid the investigator in initiating antiglycemic 
therapies. 
 
Based on the clinical experience from TAK-228 trials, most episodes of hyperglycemia 
observed occurred within the first 60 days after initiation of treatment with TAK-228 and 
have been either Grade 1 or 2 that have responded quickly to oral metformin.  
Hyperglycemia has not been dose-limiting since instituting a standard regimen for early 
treatment of hyperglycemia.   
 
All subjects developing hyperglycemia on the study should have their glucose closely 
monitored by study staff.  The investigator may choose either to continue close monitoring 
of subjects who develop Grade 1 hyperglycemia (FSG > ULN ≤ 160 mg/dL) or, 
alternatively, consider initiating treatment with an oral hypoglycemic agent, such as 


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metformin.  All subjects with Grade ≥ 2 hyperglycemia (FSG > 160 mg/dL) must be 
treated aggressively with oral hypoglycemic agents and/or insulin as clinically indicated.  
The investigator should consult an endocrinologist if needed to aid in optimizing the 
subject’s hyperglycemia treatment plan. 
 
It is recommended that subjects be treated initially with a fast acting insulin sensitizer such 
as metformin at 500 mg PO QD, and titrate up to a maximum of 1000 mg PO BID as 
needed.  Concurrent addition to metformin of DPP-4 inhibitors (eg, sitagliptin or 
vildagliptin) and/or insulin should also be considered.  Oral sulfonylureas (eg, glipizide or 
glyburide) should be used with caution due to the higher risk of inducing hypoglycemia in 
subjects.  The dose of oral hypoglycemic agents should be adjusted in subjects with renal 
insufficiency. In addition, subjects should also be encouraged to follow a low carbohydrate 
diet once hyperglycemia is first observed. 
 
Guidance for TAK-228 dose management in the event of hyperglycemia is provided in the 
table below. 
Management of Hyperglycemia 
Grade 
Description 
Treatment 
TAK-228 Dose Modification 
1 
Fasting blood sugar 
> ULN–160 mg/dL 
Continue close 
monitoring of blood 
sugars. 
Initiate oral 
hypoglycemic agent. 
None. 
2 
Fasting blood sugar 
> 160–250 mg/dL 
Initiate oral 
hypoglycemic agent 
and/or insulin if not well 
controlled on oral agent. 
None. 
≥3 
Fasting blood sugar 
> 250 mg/dL 
Initiate oral 
hypoglycemic agent 
and/or insulin. 
Hold drug until ≤ Grade 2. 
Resume TAK-228 based on timing of 
recovery: 
≤ 1 week:  resume at same dose and 
schedule; 
>1 but ≤ 3 weeks:  reduce dose  
> 3 weeks:  stop TAK-228 and discontinue 
subject from the study. 
Prevention/Prophylaxis 
 
Follow fasting serum glucose levels during clinic visits. 
 
Monitor home glucometer test results. 
 
Check HbA1c levels every 3 months during therapy. 
 
Life-style modifications, as appropriate (balanced diet, limit alcohol consumption, increase physical 
activity). 
 
Most episodes of Grade 1 and 2 hyperglycemia respond quickly to oral metformin. 
 
Early initiation of therapy is recommended to prevent higher-grade hyperglycemia. 
 
Fasting blood glucose levels ≥ 150 mg/dL by glucometer should be followed by closer monitoring of 
serum glucose and possible intervention. 
Abbreviations:  dL = deciliters; mg = milligrams; ULN = upper limit of normal. 
 
 


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6.3.2 Management of Noninfectious Pneumonitis 
Guidance for TAK-228 dose management in the event of noninfectious pneumonitis is 
shown in the table below.  
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 ADLs 
Rule out infection and 
consider treatment with 
corticosteroids until 
symptoms improve to 
≤ Grade 1. 
Interrupt TAK-228 treatment: 
When symptoms ≤Grade 1, 
reinitiate TAK-228 at a dose 
reduced by 1 level. If no recovery 
within 4 weeks, then discontinue 
TAK-228. 
3 
Symptomatic: 
Interfering with ADLs; 
Requires administration of 
O2 
Rule out infection and 
consider treatment with 
corticosteroids until 
symptoms improve to 
≤ Grade 1. 
Interrupt TAK-228 until symptoms 
resolve to ≤Grade 1.  
Consider reinitiating TAK-228 at a 
dose reduced by 1 level. 
If toxicity recurs at Grade 3, 
discontinue TAK-228. 
4 
Life-threatening: 
Ventilatory support 
indicated 
Rule out infection and 
consider treatment with 
corticosteroids. 
Discontinue TAK-228 treatment. 
Abbreviations:  ADL = activities of daily living; O2 = oxygen gas. 
 
6.3.3 Management of Hyperlipidemia 
Guidance for TAK-228 dose management in the event of hyperlipidemia is shown in the 
table below.  
Management of Hyperlipidemia 
Grade 
Description 
Treatment 
TAK-228 Dose Modification 
1 
Cholesterol: 
> ULN - 300 mg/dL 
Triglycerides: 
> 150 - 300 mg/dL 
None. 
None. 
2 
Cholesterol: 
> 300 – 400 mg/dL 
Triglycerides: 
> 300 - 500 mg/dL 
Treat hyperlipidemia 
according to standard 
guidelines. 
Triglycerides ≥ 500 mg/dl 
should be treated urgently 
due to risk of pancreatitis. 
Maintain dose if tolerable. 
 
If toxicity becomes intolerable, 
interrupt TAK-228 dosing until 
recovery to ≤ Grade 1. Reinitiate at 
same dose. 
3 
Cholesterol: 
> 400 - 500 mg/dL 
Triglycerides: 
> 500 - 1000 mg/dL 
Same as for Grade 2. 
Hold dose until recovery to 
≤ Grade 1, then restart at a dose 
reduction  
4 
Cholesterol: 
> 500 mg/dL 
Triglycerides: 
Same as for Grade 2. 
 Same as for grade 3 


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Management of Hyperlipidemia 
Grade 
Description 
Treatment 
TAK-228 Dose Modification 
> 1000 mg/dL 
Prevention/Prophylaxis 
Life-style modifications, as appropriate (balanced diet, limit consumption of alcoholic beverages, 
increase physical activity). 
Abbreviations:  dL = deciliters; mg = milligrams; ULN = upper limit of normal. 
 
6.3.4 Management of Oral Mucositis 
Guidance for TAK-228 dose management in the event of oral mucositis is provided in the 
table below.  
Management of Oral Mucositis 
Grade 
Description 
Treatment 
TAK-228 Dose Modification 
1 
Asymptomatic or mild 
symptoms 
Non-alcoholic mouth wash 
or 0.9% salt water rinse; 
Consider topical 
corticosteroids at earliest 
signs of mucositis. 
None. 
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 dose if tolerable. 
If toxicity becomes intolerable, 
interrupt TAK-228 dosing until 
recovery to ≤ Grade 1. Reinitiate at 
same dose. 
3 
Severe pain, interfering 
with oral intake 
Same as for Grade 2; 
Consider intra-lesional 
corticosteroids. 
Hold dose until recovery to ≤ Grade 
1, then restart TAK-228 at a dose 
reduced by 1 level 
4 
Life-threatening 
consequences 
Same as for Grade 2. 
Consider intra-lesional 
corticosteroids. 
Discontinue treatment. 
Prevention/Prophylaxis 
 
Consider initiation of a non-alcoholic mouthwash or 0.9% salt water rinses 4-6 times daily with 
start of therapy before signs of mucositis develop. 
 
Avoid using agents containing hydrogen peroxide, iodine, and thyme derivatives in management 
of stomatitis as they may worsen mouth ulcers. 
 
6.3.5 Management of Rash 
Guidance for TAK-228 dose adjustment for the event of rash is provided in the table 
below. 
Management of Rash 
Grade 
Description 
Treatment 
TAK-228 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 
Consider treatment with 
Hold until  Grade 2; 


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 30% body surface area 
with or without symptoms 
topical steroid 
cream/ointment, oral 
antihistamines or 
antibiotics and/or pulsed 
steroids. 
Resume TAK-228 based on 
timing of recovery: 
≤ 3 weeks: reduce dose ; 
> 3 weeks: stop TAK-228 
and discontinue subject from 
the study. 
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. 
 
6.3.6 Management of Nausea and/or Vomiting 
Guidance for TAK-228 dose adjustment for the event of nausea and/or vomiting is 
provided in the table below. 
Management of Nausea and/or Vomiting 
Grade 
Description 
Treatment 
TAK-228 Dose Modification 
 2 
Loss of appetite with or without 
decreased oral intake; 
1-5 episodes of vomiting within 
24 hours 
Maximize anti-emetic 
therapy; 
Consider IV fluid 
hydration. 
None. 
 3 
Inadequate oral intake; 
≥ 6 episodes of vomiting within 
24 hours 
Maximize anti-emetic 
therapy; 
Initiate tube feeding, 
IVF, or TPN. 
Hold until  Grade 1; 
Resume TAK-228 without dose 
modification. 
Prevention/Prophylaxis 
Prophylactic use of anti-emetic, anti-nausea, and anti-diarrheal medications are encouraged and may be 
used before each dose of TAK-228 as needed throughout the study. 
Abbreviations:  IV = intravenous; IVF = intravenous fluids; TPN = total parenteral nutrition 
 
6.3.7 Management of Cardiac Events 
 
6.3.7.1 Management of Cardiac Instability 
For subjects showing signs of cardiac instability after TAK-228 dosing, additional 
monitoring onsite before clinic discharge should be considered. 
 
6.3.7.2 Management of Left Ventricular Dysfunction 
Guidance for TAK-228 dose adjustment for the event of left ventricular dysfunction is 
provided in the table below. 
Management of Left Ventricular Dysfunction 
Grade 
Description 
TAK-228 Dose Modification 
1 
Asymptomatic decline in 
LVEF > 15% from baseline values OR; 
LVEF > 10%-15% from baseline values and is 
below institution’s LLN 
No change; continue TAK-228 at same 
dose and schedule. 


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 2 
Symptomatic cardiac dysfunction/congestive 
heart failure 
Discontinue treatment. 
Abbreviations:  LLN = lower limit of normal; LVEF = left ventricular ejection fraction. 
 
6.3.7.3 Management of QTc Prolongation 
Guidance for TAK-228 dose adjustment for the event of QTc prolongation is provided in 
the table below. 
Management of QTc Prolongation 
Grade 
Description 
Treatment 
TAK-228 Dose Modification 
2 
480 ms  QTc  
 501 ms 
Evaluate for other possible causes 
(e.g., electrolyte disturbance, 
concomitant medication, etc.) 
None; continue TAK-228 at the same 
dose and schedule. 
 3 
QTc  501 ms 
Evaluate for other possible causes 
(e.g., electrolyte disturbance, 
concomitant medication)a; 
Consider a formal consult by a 
cardiologist; 
Contact the BTCRC project manager 
who will notify the sponsor-
investigator; 
Additional ECGs may be performed at 
intervals that the treating physician 
deems clinically appropriate until 
repeated QTc measurements fall or are 
below the threshold interval that 
triggered the repeat measurement. 
Hold TAK-228 
The decision whether to reinitiate 
TAK-228 with or without dose 
reduction and additional monitoring in 
those subjects who had asymptomatic 
prolonged QTc 501 msec (Grade 3) 
that has reverted to an acceptable 
interval, have previously tolerated 
TAK-228, and appear to have 
benefitted from treatment with either 
disease control or response, will be 
agreed to by the sponsor-investigator 
and the treating physician on a case-
by-case basis. 
Abbreviations:  ECG = electrocardiogram; IV = intravenous; ms = milliseconds; QTc = QT interval 
corrected for heart rate 
a A list of medications known to prolong QTc can be found at www.torsades.org and www.QTdrugs.org. 
 
6.3.8 Management of Other Non-hematologic Toxicities (Including Asthenia, Weakness 
and Fatigue) 
Guidance on dose adjustment for subjects with other non-hematologic toxicities is 
provided below 
Management of Other Non-hematologic Toxicities (Including 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(s) 


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Management of Other Non-hematologic Toxicities (Including Asthenia, Weakness, 
and Fatigue) 
Grade 
Description 
Treatment 
Dose Modification 
until recovery to ≤Grade 1, 
then reinitiate at same dose.  
≥ 3 
Severe or medically 
significant but not 
immediately life-threatening; 
hospitalization or 
prolongation of 
hospitalization indicated 
 
Hold TAK-228(s)  until recovery 
to ≤ Grade 1. Reinitiate TAK-228 
at dose reduced by 1 level  
 
6.3.9 Management of Aspartate Aminotransferase/Alanine Aminotransferase Elevations 
 
Guidance on dose adjustment for subjects with AST/ALT elevations is provided below 
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 subjects for other 
causes of transaminitis (eg, 
past medical history, 
concomitant medications). 
None 
3 
>5 to 20ULN; >5ULN for 
>2 weeks 
Same as for Grade 2. 
Hold TAK-228(s) until 
≤Grade 1; Restart TAK-228 at 
the same dose; 
4 
>20ULN 
Same as for Grade 2. 
Stop TAK-228 and discontinue 
subjects from the study 
Prevention/Prophylaxis: 
Ensure proper screening of subjects for study participation. 
LFTs=liver function tests, ULN=upper limit of normal. 
 


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6.4 
Sorafenib Dose Modifications 
 
Dose adjustment for sorafenib will be per standard of care.  
 
Table of Dose Adjustments for Sorafenib Dosing on a BID Scheduling  
Dose Level 
Sorafenib Dose 
1 
400mg PO BID  
-1 
400mg PO QD (once a day) 
-2 
400mg PO QOD (every other day) 
-3 
Discontinue 
Level 1 is the starting dose.
 
 
6.5 
Management of Sorafenib Clinical Events 
 
6.5.1 Sorafenib Dose Modifications for Skin Toxicity 
 
Dose modifications for Rash (Maculopapular) or Palmar-Plantar 
Erythrodysesthesia (Hand-Foot Syndrome; HFSR) 
Grade 
Appearance 
Sorafenib Dose Modification 
Grade 2 
1st 
Interrupt sorafenib until skin toxicity improves to  
≤ grade 1, then resume sorafenib at the previous dose 
level.
2nd or 3rd 
Interrupt sorafenib until skin toxicity improves to ≤ 
grade 1, then resume sorafenib at one reduced dose 
level
4th 
Discontinue all protocol therapy 
Grade 3 
1st or 2nd 
Interrupt sorafenib until skin toxicity improves to  
≤ grade 1, then resume sorafenib at one reduced dose 
level
3rd 
Discontinue all protocol therapy 
 
If sorafenib is interrupted for more than 3 weeks for skin toxicity, discontinue all protocol 
therapy. 
 
Following a full cycle of reduced dose sorafenib with no rash (maculopapular) or HFSR of 
≥ grade 1 severity, the dose of sorafenib may be re-escalated to the prior dose level.  
 
6.5.1.1 Management of Skin Toxicity:  
At first occurrence of HFSR, independent of grade, supportive measures such as topical 
emollients, low potency steroids, or urea-containing cream should be administered.  
 


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6.5.2 Sorafenib Dose Modifications for Hypertension 
 
Description 
Sorafenib Dose Modification 
> 140/90 and ≤ 160/100 
Continue sorafenib. Consider adding or adjusting 
anti-hypertensive medications.
persistent (> 160/100) or 
symptomatic hypertension
Interrupt sorafenib. Resume when blood pressure 
improves to ≤160/100. 
 
If sorafenib is interrupted for more than 3 weeks, contact the BTCRC Project Manager 
regarding continuation of therapy. 
 
6.5.3 Other Non-hematologic toxicities 
 
Grade 3: For other grade 3 toxicity considered at least possibly related to sorafenib, 
interrupt sorafenib until toxicity improves to ≤ grade 1.  
If sorafenib is interrupted for more than 3 weeks, discontinue all protocol therapy. 
 
Grade 4: Discontinue all protocol therapy 
 
6.5.4 Hematology toxicities 
 
Grade 4 neutropenia, thrombocytopenia, neutropenic fever: Interrupt sorafenib until 
≤ grade 2, and then resume with one dose level reduction of sorafenib for all subsequent 
doses.  


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7 
STUDY CALENDAR & EVALUATIONS 
Study Day 
Prior to 
registration
Cycle 1 (±3) 
Cycle = 28 days3
Cycle 2 (±3) 
Cycle 3+ 
(±3) 
Every 2 
cycles
End of 
treatment
Follow 
Up
-28 days 
D 
15
D 
8
D 
15
D 
22
D 
1
D
8
D 
15 
D 
22
Day 1  
Day 1 (±7) 
C3, 5, 7 . . .
30 days (±7) 
post Tx
(±14) 
TESTS AND OBSERVATIONS  
 
Medical History 
X
 
Physical Exam 
X
X
X
X
X
X
X 
X
X
Height, SpO21 
X
 
Vital Signs2 
X
X
X
X
X
X
X 
X
X
ECOG Performance Status 
X
X
X
X
X
X
X 
X
X
Adverse Events 
X
X
X
X
X
X 
X
X
Concomitant Medication Log 
X
X
X
X
X
X
X 
X
Drug Diary Review 
X
X
X
X
X
X 
X
12 Lead ECG 
X
 
LABORATORY ASSESSMENTS3 
 
Complete Blood Count + Differential4 
X
X
X
X
X 
X
Comprehensive Metabolic Panel5 
X
X
X
X
X 
X
Urinalysis 
X
X
X
 
X
LDH 
X
X
 
X
Calculated Creatinine Clearance 
X
X
 
X
HBsAg, HBcAb, HCVAb18 
X
 
PT, INR, PTT 
X
X
 
X
TSH 
X
X
 
X
Alpha-fetoprotein 
X
X
 
X
Child Pugh Score (see SPM) 
X
X
 
X
Pregnancy test (WOCBP)19 
-7days
X
X
 
X
HbA1c 
X
 
Fasting Lipid Profile6 
X
 
TAK-228 SUBJECTS ONLY 
 
12 Lead ECG17 
X
X
 
X
HbA1c 
 
q3 cycles
Fasting serum glucose16  
X16 
X
X
X
X16 
X 
X
At-home fasting blood glucose monitoring 
 
X, daily throughout treatment 
 
 
 
Fasting Lipid Profile6 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
DISEASE ASSESSMENT 
 
CT (arterial, venous phase of liver)7 or MRI
X
 
X
None
[X]15


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Study Day 
Prior to 
registration
Cycle 1 (±3) 
Cycle = 28 days3
Cycle 2 (±3) 
Cycle 3+ 
(±3) 
Every 2 
cycles
End of 
treatment
Follow 
Up
-28 days 
D 
15
D 
8
D 
15
D 
22
D 
1
D
8
D 
15 
D 
22
Day 1  
Day 1 (±7) 
C3, 5, 7 . . .
30 days (±7) 
post Tx
(±14) 
TREATMENT 
 
TAK-2288 (all Phase I; Phase II Arm A) 
X
X
X
X
X
X 
X 
X
D1, 8, 15, 22 
Sorafenib (Phase II Arm B) 
X
CORRELATIVE STUDIES: PHASE II SUBJECTS ONLY
 
Pharmacokinetics9 (1st 10 pts. in Arm A) 
 
D1
D2
 
 
 
D1
D2
 
 
 
 
 
 
 
HCC unstained slides or new biopsy10 
X
 
Central analysis of CT/MRI images11 
X
 
Best Resp.
At PD
BANKING SAMPLES: PHASE II SUBJECTS ONLY
 
Whole Blood12 
X
 
Unstained slides from HCC tumor13 
X
 
Serum and plasma14 
X
 
X
FOLLOW-UP15 
 
Survival 
 
X
Footnotes: 
1: Subjects with O2 saturation < 90% by ABG (Arterial Blood Gas) analysis or pulse oximetry on room air are excluded. See section 3.2.11.3. 
2: Vital signs to include: pulse, blood pressure and weight. 
3:  C1D1 labs must be verified before subject begins study drug. For subsequent cycles, labs may be obtained up to 3 days prior to day of treatment. 
Screening labs performed within 7 days of C1D1 do not need to be repeated. 
4: Complete Blood Count with differential to include: absolute neutrophil count (ANC), platelet and hemoglobin. 
5: Comprehensive Metabolic Panel to include: Na, K, Cl, CO2, total bilirubin, direct bilirubin, total protein, albumin, alk phos, AST, ALT, creatinine, 
BUN, calcium, Mg, Phos, and glucose. 
6: Fasting lipid profile to include: total cholesterol, LDL, HDL, total triglycerides 
7: Preferably CT chest/abdomen/pelvis with triphasic liver scan. If CT contrast is contraindicated despite the use of antihistamines and steroids, CT chest 
without contrast and MRI of abdomen and pelvis is allowed.  
8: TAK-228 will be administered only to eligible subjects under the supervision of the investigator or identified sub-investigator(s) during Cycle 1 for all 
TAK-228 subjects and during Cycle 2 Day 1 for the first 10 subjects randomized to Phase II arm A; subsequent doses may be taken at home. Sorafenib 
will be taken at home twice daily. 
9: Phase II Arm A subjects only: Pharmacokinetic sampling will be performed on the first 10 subjects randomized to Arm A. PKs will be collected on 
C1D1-2 and C2D1-2 at the following time points: pre-dose, 0.5, 1, 2, 4, 6, 8, and 24 hours post-dose. See Clinical Laboratory Manual (CLM) for 
collection, processing, labeling and shipping instructions.  
10: Phase II subjects only: Unstained slides will be collected and evaluated for mTOR and PI3K/Akt expression and phosphoproteins via 
immunohistochemistry (IHC) and oncogene expression affecting mTOR activation via targeted deep sequencing assay. If the subject does not have an 


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HCC archived tumor tissue block available, the subject must have a biopsy prior to registration to obtain tumor tissue for correlative studies. See CLM 
for collection, labeling and shipping instructions. 
11: Phase II subjects only: CT/MRI images from baseline, best response and disease progression scans will be submitted for central analysis to assess 
tumor necrosis and modified RECIST (mRECIST) criteria.  
12: Phase II subjects only: Submission of whole blood for banking is to be collected at Pre-Treatment Cycle 1 Day 1. See CLM for collection, processing, 
labeling and shipping instructions. 
13: Phase II subjects only: Submission of unstained slides from an archived FFPE tumor block for banking is requested. See CLM for collection, labeling 
and shipping instructions. 
14: Phase II subjects only: Submission of serum and plasma are to be collected at Pre-Treatment Cycle 1 Day 1 and at the End of Treatment visit. See 
CLM for collection, labeling, processing and shipping instructions. 
15: Post treatment follow up: If treatment ended for reasons other than disease progression: every 3 months for 1 year, then every 6 months until 
progression. After disease progression, report survival status every 6 months until 2 years after progression. 
16: TAK-228 subjects only: Fasting serum glucose testing will be performed at each clinic visit. In addition, the first 10 subjects randomized to Phase II 
Arm A will have fasting serum glucose testing on Cycle 1 Days 1 and 2 and Cycle 2 Days 1 and 2. 
17: TAK-228 subjects only: 12-lead ECGs will be collected at pre-dose Cycle 1 Day 1, pre-dose Cycle 2 Day 1, and during the EOT visit. When the timing 
of an ECG coincides with blood samples for PK or tumor biopsy, the ECG should be completed first. 
18: Hepatitis B surface antigen (HBsAg), Hepatitis B core antibody (HBcAb), Hepatitis C antibody (HCVAb). 
19: Pregnancy test for women of childbearing potential at screening and prior to starting each cycle. Serum pregnancy test at screening; urine pregnancy 
test is acceptable for all other time points. A positive urine test should be confirmed with a serum test. 
 


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7.1 
Screening 
 
7.1.1 Within 28 days prior to registration for protocol therapy unless otherwise specified:  
 Medical history 
 Physical exam 
 Pulse, blood pressure, height, weight, O2 saturation 
 ECOG performance status 
 Concomitant medications 
 12-lead ECG 
 Complete blood count with differential and platelets (absolute neutrophil count (ANC), 
platelets and hemoglobin) 
 Comprehensive metabolic panel (Na, K, Cl, CO2, total bilirubin, direct bilirubin, total 
protein, albumin, alk phos, AST, ALT, creatinine, BUN, calcium, Mg, Phos, and 
glucose) 
 Urinalysis 
 LDH 
 Calculated creatinine clearance (Cockcroft Gault) 
 Hepatitis B surface antigen, Hepatitis B core antibody, Hepatitis C antibody 
 PT, INR, PTT 
 TSH 
 Alpha-fetoprotein 
 Child-Pugh Score (see SPM) 
 Serum pregnancy test for females of childbearing potential (within 7 days prior to 
registration) 
 HbA1c 
 Fasting lipid profile (total cholesterol, LDL, HDL, total triglycerides) 
 CT or MRI 
o Preferably CT chest/abdomen/pelvis with triphasic liver scan. If CT contrast is 
contraindicated despite the use of antihistamines and steroids, CT chest without 
contrast and MRI of abdomen and pelvis is allowed.  The same imaging modality 
should be used throughout the study.  
 Phase II subjects only:  
o An archived HCC tumor tissue block must be identified prior to registration. If an 
archived HCC tumor tissue block is not available, the subject must have a biopsy 
performed prior to registration to obtain HCC tumor tissue for correlative analysis. 
 
7.2 
On Treatment 
 
7.2.1 Cycle 1 Day 1: 
Note: Cycle 1 Day 1 lab testing need not be repeated if completed within 7 days of starting 
protocol therapy. 
 
 Physical exam 
 Pulse, blood pressure, weight 
 ECOG performance status 


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 Baseline signs/symptoms 
 Concomitant medications 
 Drug diary distribution/education 
 Complete blood count with differential (absolute neutrophil count (ANC), platelets and 
hemoglobin) 
 Comprehensive metabolic panel  
 Urinalysis 
 Drug administration as outlined in Section 6 and Study Calendar  
 Phase II subjects only: 
o Correlative and banking samples. See section 9.0 and CLM for specific 
instructions. 
 TAK-228 subjects only:  
o 12-lead ECG at pre-dose. When the timing of an ECG coincides with blood 
samples for PK, the ECG should be completed first. 
o Fasting serum glucose will be performed at each clinic visit. 
 Cycle 1 Days 1 and 2: Fasting serum glucose (first 10 Phase II Arm A subjects 
only). 
o At-home fasting blood glucose monitoring will occur daily. 
o Cycle 1 Day 1-2: PK sampling (first 10 Phase II Arm A subjects only). See section 
9.0 and CLM for specific instructions. 
 
7.2.2 Cycle 1 Day 8 (±3 days): 
 Physical exam 
 Pulse, blood pressure, weight 
 ECOG performance status 
 Adverse event assessment 
 Concomitant medications 
 Drug diary review 
 Drug administration as outlined in Section 6 and Study Calendar 
 TAK-228 subjects only:  
o Fasting serum glucose will be performed at each clinic visit. 
o At-home fasting blood glucose monitoring will occur daily. 
 
7.2.3 Cycle 1 Day 15 (±3 days): 
 Physical exam 
 Pulse, blood pressure, weight 
 ECOG performance status 
 Adverse events 
 Concomitant medications 
 Drug diary review 
 Complete blood count with differential (absolute neutrophil count (ANC), platelets and 
hemoglobin) 
 Comprehensive metabolic panel  
 Drug administration as outlined in Section 6 and Study Calendar  
 TAK-228 subjects only:  


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o Fasting serum glucose will be performed at each clinic visit. 
o At-home fasting blood glucose monitoring will occur daily. 
 
7.2.4 Cycle 1 Day 22 (±3 days): 
 Physical exam 
 Pulse, blood pressure, weight 
 ECOG performance status 
 Adverse event assessment 
 Concomitant medications 
 Drug diary review 
 Drug administration as outlined in Section 6 and Study Calendar 
 TAK-228 subjects only:  
o Fasting serum glucose will be performed at each clinic visit. 
o At-home fasting blood glucose monitoring will occur daily. 
 
7.2.5 Cycle 2 Day 1 (±3 days): 
 Physical exam 
 Pulse, blood pressure, weight 
 ECOG performance status 
 Adverse Events 
 Concomitant medications 
 Drug diary review 
 Complete blood count with differential (absolute neutrophil count (ANC), platelets and 
hemoglobin) 
 Comprehensive metabolic panel  
 Urinalysis 
 LDH 
 Calculated creatinine clearance (Cockcroft Gault) 
 PT, INR, PTT 
 TSH 
 Alpha-fetoprotein 
 Child-Pugh Score (see SPM) 
 Urine pregnancy test for women of childbearing potential. 
 Drug administration as outlined in Section 6 and Study Calendar 
 TAK-228 subjects only:  
o 12-lead ECG at pre-dose.  When the timing of an ECG coincides with blood 
samples for PK, the ECG should be completed first. 
o Fasting serum glucose will be performed at each clinic visit. 
 Cycle 2 Days 1 and 2: Fasting serum glucose (first 10 Phase II Arm A subjects 
only). 
o At-home fasting blood glucose monitoring will occur daily. 
o Fasting lipid profile Cycle 2 Day 1 
o Cycle 2 Day 1-2: PK sampling (first 10 Phase II Arm A subjects only). See section 
9.0 and CLM for specific instructions. 
 


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7.2.6 Cycle 2 Day 8 (±3 days): 
 Drug administration as outlined in Section 6 and Study Calendar 
 
7.2.7 Cycle 2 Day 15 (±3 days): 
 Physical exam 
 Pulse, blood pressure, weight 
 ECOG performance status 
 Adverse events 
 Concomitant medications 
 Drug diary review 
 Complete blood count with differential (absolute neutrophil count (ANC), platelets and 
hemoglobin) 
 Comprehensive metabolic panel  
 Drug administration as outlined in Section 6 and Study Calendar  
 TAK-228 subjects only:  
o Fasting serum glucose will be performed at each clinic visit. 
o At-home fasting blood glucose monitoring will occur daily. 
 
7.2.8 Cycle 2 Day 22 (±3 days): 
 Drug administration as outlined in Section 6 and Study Calendar 
 
7.2.9 Cycle 3+ Day 1 (±3 days): 
 Physical exam 
 Pulse, blood pressure, weight 
 ECOG performance status 
 Adverse Events 
 Concomitant medications 
 Drug diary review 
 Complete blood count with differential (absolute neutrophil count (ANC), platelets and 
hemoglobin) 
 Comprehensive metabolic panel  
 Urinalysis 
 LDH 
 Calculated creatinine clearance (Cockcroft Gault) 
 PT, INR, PTT 
 TSH 
 Alpha-fetoprotein 
 Child-Pugh Score (see SPM) 
 Urine pregnancy test for women of childbearing potential. 
 Drug administration as outlined in Section 6 and Study Calendar 
 TAK-228 subjects only:  
o Fasting serum glucose will be performed at each clinic visit. 
o At-home fasting blood glucose monitoring. If no irregularities in the fasting blood 
glucose level are observed during a minimum of two consecutive months, the 


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frequency of in-home fasting blood glucose testing may be reduced to a minimum 
frequency of once weekly if the investigator approves. See section 6.3.1. 
o Fasting lipid profile Day 1 of each cycle 
o Every 3 cycles (C3, 6, 9, etc.): HbA1c 
 
7.2.10 Day 1 of every 2 cycles (±7 days) (C3, 5, 7, etc.): 
 CT (arterial and venous phase of liver) or MRI 
o Preferably CT chest/abdomen/pelvis with triphasic liver scan. If CT contrast is 
contraindicated despite the use of antihistamines and steroids, CT chest without 
contrast and MRI of abdomen and pelvis is allowed. 
 
7.3 
Off Treatment 
 
7.3.1 Protocol therapy discontinuation: 
A subject will be discontinued from the protocol therapy under the following 
circumstances: 
 
If there is evidence of disease progression  
 
If the treating physician thinks a change of therapy would be in the best interest of the 
subject 
 
If the subject requests to discontinue protocol therapy 
 
If the protocol therapy exhibits unacceptable toxicity 
 
If a female subject becomes pregnant  
 
If protocol therapy is interrupted for ≥ 28 days for TAK-228, or ≥ 21 days for sorafenib 
due to a treatment-related adverse event.  
 
If the subject demonstrates serious or continuing non-compliance 
 
Subjects can stop study participation at any time. However, if they decide to stop, subjects 
will continue to be followed per section 7.4, Follow-Up, unless the subject has also 
withdrawn consent for further follow-up.  
 
7.3.2 End of Treatment 30 days (±7 days) after final protocol therapy dose 
At the time of protocol therapy discontinuation, all study procedures outlined for the End 
of Treatment visit should be performed. The primary reason for subject’s discontinuation 
should be recorded in the source documents and eCRF. 
 
 Physical exam 
 Pulse, blood pressure, weight 
 ECOG performance status 
 Adverse Events 
 CT/MRI images from baseline, best response and disease progression scans will be 
submitted for central analysis to assess tumor necrosis and modified RECIST 
(mRECIST) criteria 
 TAK-228 subjects only:  
o 12 lead ECG 
 Phase II subjects only:  
o 
Banking samples. See section 9.0 and CLM for specific instructions. 


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7.4 
Follow-up (±14 days) 
If treatment ended for reasons other than disease progression, subjects will be followed for 
disease progression and survival every 3 months for 1 year, then every 6 months until 
progression.  
 
After disease progression, survival status should be reported every 6 months until 2 years 
after progression. 
 
8 
CRITERIA FOR DISEASE EVALUATION 
 
8.1 
Definitions Associated with Response Evaluation Criteria in Solid Tumors (RECIST) 
version 1.1 [Eur J Ca 45:228-247, 2009]. 
 
8.1.1 
Measurable disease: The presence of at least one measurable lesion. If the measurable 
disease is restricted to a solitary lesion, its neoplastic nature should be confirmed by 
cytology/histology.  
 
8.1.2 
Measurable lesions: Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as ≥20 mm by chest 
x-ray, as ≥10 mm with CT scan, or ≥10 mm with calipers by clinical exam.  All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters). 
 
Non-measurable lesions: All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥ 10 to <15 mm short axis), 
are considered non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
and abdominal masses (not followed by CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor non-measurable) 
since they are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same subject, these are preferred for selection as target 
lesions. 
 
8.1.3 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a 
lymph node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm).  At baseline and in follow-up, only 
the short axis will be measured and followed. 
 
8.1.4 
Baseline documentation of “Target” and “Non-Target” lesions:  
 
Target lesions. All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target 


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lesions and recorded and measured at baseline.  Target lesions should be selected on the 
basis of their size (lesions with the longest diameter), be representative of all involved 
organs, but in addition should be those that lend themselves to reproducible repeated 
measurements.  It may be the case that, on occasion, the largest lesion does not lend itself 
to reproducible measurement in which circumstance the next largest lesion which can be 
measured reproducibly should be selected.  A sum of the diameters (longest for non-nodal 
lesions, short axis for nodal lesions) for all target lesions will be calculated and reported 
as the baseline sum diameters.  If lymph nodes are to be included in the sum, then only the 
short axis is added into the sum.  The baseline sum diameters will be used as reference to 
further characterize any objective tumor regression in the measurable dimension of the 
disease. 
 
Non-target lesions.  All other lesions (or sites of disease) including any measurable 
lesions over and above the 5 target lesions should be identified as non-target lesions and 
should also be recorded at baseline.  Measurements of these lesions are not required, but 
the presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow-up. 
 
8.2 
Response Criteria 
 
8.2.1 Evaluation of target lesions 
Complete Response (CR) 
Disappearance of all target lesions.  Any 
pathological lymph nodes (whether target or non-
target) must have reduction in short axis to <10 
mm.
Partial Response (PR) 
At least a 30% decrease in the sum of the diameters 
of target lesions, taking as reference the baseline 
sum diameters
Progressive Disease (PD) 
At least a 20% increase in the sum of the diameters 
of target lesions, taking as reference the smallest 
sum on study (this includes the baseline sum if that 
is the smallest on study).  In addition to the relative 
increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm.  (Note:  the 
appearance of one or more new lesions is also 
considered progressions).
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as 
reference the smallest sum diameters while on study
 
 
8.2.2 Evaluation of non-target lesions 
 
Complete Response (CR) 
Disappearance of all non-target lesions and 
normalization of tumor marker level.  All lymph 
nodes must be non-pathological in size (<10 mm 
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Note:  If tumor markers are initially above the 
upper normal limit, they must normalize for a 
subject to be considered in complete clinical 
response.
Non-CR/ Non-PD 
Persistence of one or more non-target lesion(s) 
and/or maintenance of tumor marker level above 
the normal limits
Progressive Disease (PD) 
Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target 
lesions.  Unequivocal progression should not 
normally trump target lesion status.  It must be 
representative of overall disease status change, not 
a single lesion increase.
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the Sponsor-Investigator. 
8.3 
Evaluation of best overall response 
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for PD the smallest measurements recorded since the 
treatment started). In general, the subject's best response assignment will depend on the 
achievement of both measurement and confirmation criteria. 
 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall 
Response 
CR 
CR
No
CR 
CR 
Non-CR/ Non-PD
No
PR 
 
Not evaluated
No
PR 
PR 
Non-CR/ Non-PD/ not 
evaluated
No 
PR 
SD 
Non-CR/ Non-PD/ not 
evaluated
No 
SD 
PD 
Any
Yes or No
PD 
Any 
PD*
Yes or No
PD 
Any 
Any
Yes
PD 
 
*In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
 
Subjects with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be classified as having “symptomatic 
deterioration.” Every effort should be made to document the objective progression even after 
discontinuation of treatment. 
 
In some circumstances, it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends on this determination, it is recommended that 


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the residual lesion be investigated (fine needle aspirate/biopsy) to confirm the complete response 
status. 
 
8.4 
Definitions for Response Evaluation –RECIST version 1.1 
 
8.4.1 First Documentation of Response: 
The time between initiation of therapy and first documentation of PR or CR. 
 
8.4.2 Confirmation of Response: 
To be assigned a status of complete or partial response, changes in tumor measurements 
must be confirmed by repeat assessments performed no less than four weeks after the 
criteria for response are first met. 
 
8.4.3 Duration of Response: 
Duration of overall response – the period measured from the time that measurement 
criteria are met for complete or partial response (whichever status is recorded first) until 
the date that recurrent or progressive disease is objectively documented (taking as 
reference for progressive disease the smallest measurements recorded since treatment 
started). 
 
8.4.4 Duration of Overall Complete Response: 
The period measured from the time that measurement criteria are met for complete 
response until the first date that progressive disease is objectively documented. 
 
8.4.5 Objective Response Rate:  
The objective response rate is the proportion of all subjects with confirmed PR or CR 
according to RECIST v1.1, from the start of treatment until disease progression/recurrence 
(taking as reference for progressive disease the smallest measurements recorded since the 
start of treatment). 
 
8.4.6 Disease Control Rate: 
The disease control rate is the proportion of all subjects with stable disease (SD) for 8 
weeks, or partial response (PR), or complete response (CR) according to RECIST v1.1, 
from the start of treatment until disease progression/recurrence (taking as reference for 
progressive disease the smallest measurements recorded since the start of treatment). 
 
8.4.7 Time To Progression: 
A measurement from the date of randomization until the criteria for disease progression is 
met as defined by RECIST 1.1. Subjects who have not progressed or have died due to any 
cause will be right-censored at the date of the last disease evaluation or date of death. 
 
8.4.8 Progression Free Survival: 
A measurement from the date of randomization until the criteria for disease progression is 
met as defined by RECIST 1.1 or death occurs. Subjects who have not progressed will be 
right-censored at the date of the last disease evaluation. 
 
8.4.9 Overall Survival: 


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Overall Survival is defined by the date of randomization to date of death from any cause. 
 
8.5 
Methods of Measurement 
 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 28 days before the beginning of the treatment. 
 
Imaging-based evaluation is preferred to evaluation by clinical examination unless the lesion(s) 
being followed cannot be imaged but are assessable by clinical exam. The same imaging modality 
must be used throughout the study to measure disease. 
 
8.5.1 CT and MRI: 
CT and MRI are the best currently available and most reproducible methods for measuring 
target lesions. This guideline has defined measurability of lesions on CT scan based on the 
assumption that CT slice thickness is 5 mm or less.  If CT scans have slice thickness 
greater than 5 mm, the minimum size for a measurable lesion should be twice the slice 
thickness.  MRI is also acceptable in certain situations (e.g. for body scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement.  Furthermore, the 
availability of MRI is variable globally.  As with CT, if an MRI is performed, the technical 
specifications of the scanning sequences used should be optimized for the evaluation of the 
type and site of disease.  Furthermore, as with CT, the modality used at follow-up should 
be the same as was used at baseline and the lesions should be measured/assessed on the 
same pulse sequence.  It is beyond the scope of the RECIST guidelines to prescribe 
specific MRI pulse sequence parameters for all scanners, body parts, and diseases.  Ideally, 
the same type of scanner should be used and the image acquisition protocol should be 
followed as closely as possible to prior scans.  Body scans should be performed with 
breath-hold scanning techniques, if possible. 
 
PET-CT.  At present, the low dose or attenuation correction CT portion of a combined 
PET-CT is not always of optimal diagnostic CT quality for use with RECIST 
measurements.  However, if the site can document that the CT performed as part of a PET-
CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), then the 
CT portion of the PET-CT can be used for RECIST measurements and can be used 
interchangeably with conventional CT in accurately measuring cancer lesions over time.  
Note, however, that the PET portion of the CT introduces additional data which may bias 
an investigator if it is not routinely or serially performed.   
 
8.5.2 Chest X-Ray: 
Lesions on chest x-ray are acceptable as measurable lesions when they are clearly defined 
and surrounded by an aerated lung (CT is preferable).  
 


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8.5.3 Clinical Examination: 
Clinically detected lesions will only be considered measurable when they are superficial 
(e.g. skin nodules and palpable lymph nodes). For skin lesions, documentation by color 
photography, including a ruler to estimate size of the lesion, is recommended. Photographs 
should be retained at the institution. 
 
8.5.4 Cytology and Histology: 
Cytologic and histologic techniques can be used to differentiate between complete and 
partial responses in rare cases (e.g. after treatment to differentiate residual benign lesions 
and residual malignant lesions in germ cell tumors). Cytologic confirmation of the 
neoplastic nature of any effusion that appears or worsens during treatment is required when 
the measurable tumor has met response or stable disease criteria. 
 
8.6 
mRECIST for HCC: Assessment of Tumor Lesions at Baseline 
According to RECIST, tumor lesions are categorized at baseline as follows: measurable 
(lesions that can be accurately measured in at least one dimension as ≥1 cm with a spiral 
CT scan) or nonmeasurable [all other lesions, including small lesions (longest diameter <1 
cm with spiral CT scan) and truly nonmeasurable lesions]. The original RECIST 
publication states that all measurable lesions up to a maximum of five lesions per organ and 
10 lesions in total, representative of all involved organs, should be identified as target 
lesions and recorded and measured at baseline. The recent 1.1 release of RECIST has 
reduced the number of lesions to select as target lesions to a maximum of two lesions per 
organ and five lesions in total.42 In fact, analyses on a large prospective database has shown 
that assessment of five versus 10 lesions per patient did not affect the overall response rate, 
and that progression-free survival was only minimally affected.43 Target lesions should be 
selected on the basis of their size (those with the longest diameter) and their suitability for 
accurate repeated measurements. All other lesions (or sites of disease) should be identified 
as nontarget lesions and should also be recorded at baseline. Measurements of these lesions 
are not required, but the presence or absence of each should be noted throughout follow-up. 
 
It is our understanding that the measurement of the longest viable tumor diameter for the 
assessment of response according to mRECIST44 can be only applied in case of typical 
lesions. Conversely, for non- enhancing atypical lesions, as well as for any extrahepatic 
neoplastic niches, the measurements of the longest overall tumor diameter as per 
conventional RECIST should prevail. 
 
To be selected as a target lesion using mRECIST, an HCC lesion should meet all the 
following criteria: 
 
 The lesion can be classified as a RECIST measurable lesion (i.e., the lesion can be 
accurately measured in at least one dimension as 1 cm or more). 
 The lesion is suitable for repeat measurement. 
 The lesion shows intratumoral arterial enhancement on contrast-enhanced CT or MRI. 
 
It is important to point out that only well-delineated, arterially enhancing lesions can be 
selected as target lesions for mRECIST. This may not be the case of infiltrative-type HCC. 
Infiltrative-type HCC should be considered as a nontarget lesion when the mass shows ill-


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defined borders and therefore does not appear to be suitable for accurate and repeat 
measurements. HCC lesions previously treated with locoregional or systemic treatments 
may or may not be considered as suitable to be selected as target lesions for mRECIST: if 
the lesion shows a well-delineated area of viable (contrast enhancement in the arterial 
phase) tumor that is at least 1 cm in longest diameter, then it can be selected as a target 
lesion. In contrast, if the lesion is poorly demarcated or exhibits atypical enhancement as a 
result of the previous intervention, then it cannot be selected as a target lesion for 
mRECIST. 
 
8.7 
mRECIST: Defining Treatment Response and Tumor Progression 
 
8.7.1 Target Lesions Response 
According to RECIST, complete response is the disappearance of all target lesions; partial 
response is at least a 30% decrease in the sum of the longest diameter of target lesions, 
taking as reference the baseline sum longest diameter; progressive disease is at least a 20% 
increase in the sum of the longest diameter of target lesions, taking as reference the 
smallest sum longest diameter recorded since when treatment started or the appearance of 
one or more new lesions; stable disease is neither sufficient shrinkage to qualify for partial 
response nor sufficient increase to qualify for progressive disease, taking as reference the 
smallest sum longest diameter since the treatment started. 
The mRECIST for HCC has introduced the following amendments to RECIST in the 
determination of tumor response for target lesions (see table below): 
 
Complete response: the disappearance of any intratumoral arterial enhancement in all 
target lesions 
 
Partial response: at least a 30% decrease in the sum of diameters of viable (contrast 
enhancement in the arterial phase) target lesions, taking as reference the baseline sum 
of the diameters of target lesions 
 
Progressive disease: an increase of at least 20% in the sum of the diameters of viable 
(enhancing) target lesions, taking as reference the smallest sum of the diameters of 
viable (enhancing) target lesions recorded since the treatment started 
 
Stable disease: any cases that do not qualify for either partial response or progressive 
disease 
 
 


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Assessment of Target Lesion Response: Conventional RECIST and mRECIST Assessment for HCC 
Following the AASLD-JNCI Guideline 
RECIST 
mRECIST for HCC 
CR = Disappearance of all target lesions 
CR = Disappearance of any intratumoral arterial 
enhancement in all target lesions 
PR = At least a 30% decrease in the sum of 
diameters of target lesions, taking as reference 
the baseline sum of the diameters of target lesions
PR = At least a 30% decrease in the sum of diameters of 
viable (enhancement in the arterial phase) target lesions, 
taking as reference the baseline sum of the diameters of 
target lesions
SD = Any cases that do not qualify for either 
partial response or progressive disease 
SD = Any cases that do not qualify for either partial 
response or progressive disease 
PD = An increase of at least 20% in the sum of 
the diameters of target lesions, taking as 
reference the smallest sum of the diameters of 
target lesions recorded since treatment started 
PD = An increase of at least 20% in the sum of the 
diameters of viable (enhancing) target lesions, taking as 
reference the smallest sum of the diameters of viable 
(enhancing) target lesions recorded since treatment 
started
AASLD, American Association for the Study of Liver Diseases; JNCI, Journal of the National Cancer 
Institute; HCC, hepatocellular carcinoma; mRECIST, modified Response Evaluation Criteria in Solid 
Tumors; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease.
 
The measurement of the longest diameter of the viable tumor may be challenging in 
lesions showing partial internal necrosis (Fig. 1). The following points should be taken into 
account in such cases: 
 
The measurement of the viable tumor should be performed on CT or MRI obtained in 
the arterial phase, when the contrast between viable vascularized tumor tissue and 
nonenhancing necrotic tissue is the highest. 
 
The longest diameter of the viable tumor is not necessarily located in the same scan 
plane in which the baseline diameter was measured: a thorough careful evaluation of 
the CT or MRI scans is required. 
 
The measurement of the viable tumor diameter should not include any major 
intervening areas of necrosis. 


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It is important to point out that a reduction of at least 30% in the diameter of the viable 
tumor (the threshold required to declare partial response according to mRECIST) 
corresponds to a decrease of 65% in viable tumor volume. In contrast, an increase of at 
least 20% in the diameter of the viable tumor (the threshold required to declare progressive 
disease according to mRECIST) corresponds to an increase of at least 73% in viable tumor 
volume. The panel acknowledged that direct volumetric measurement to identify partial 
response and progression should be a priority in future clinical trial research. 
 
8.7.2 Non-Target Lesions Response 
The RECIST guideline provides the following definitions of the criteria used to determine 
the objective tumor response for nontarget lesions: complete response is the disappearance 
of all nontarget lesions; incomplete response/stable disease is the persistence of one or 
more nontarget lesions; and progressive disease is the appearance of one or more new 
lesions and/or unequivocal progression of existing nontarget lesions. 
 
According to mRECIST for HCC, tumor necrosis should be taken into account when 
assessing the response of nontarget lesions. The disappearance of intratumoral arterial 
enhancement in nontarget lesions should be considered equivalent to the disappearance of 
nontarget lesions, and therefore, should declare complete response of nontarget lesions. 
The persistence of intratumoral arterial enhancement in one or more nontarget lesions 
should be considered equivalent to persistence of one or more nontarget lesions, and 
therefore, should declare incomplete response / stable disease. The appearance of one or 
more new lesions and/or unequivocal progression of existing nontarget lesions should 
declare progressive disease. 
 
Special recommendations for the assessment of tumor response in nontarget lesions in 
subjects with HCC and cirrhosis can be made regarding the following points: 
 
1. Portal vein thrombosis. Malignant portal vein thrombosis should be considered a 
nonmeasurable lesion due to the difficulty in performing consistent measurements of 
the malignant thrombus during the course of the treatment. Measurements of the extent 


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of the malignant thrombus may be impaired by the possible presence of a bland 
component of the thrombosis. 
2. Porta hepatis lymph node. Lymph nodes detected at the portal hepatis can be 
considered as malignant if the lymph node short axis is at least 20 mm. Evidence of 
reactive lymph nodes at the porta hepatis, in fact, is a common finding in patients with 
cirrhosis regardless of the presence of an HCC. The short axis of the node is the 
diameter normally used by radiologists to judge if a node is involved by solid tumor. 
3. Pleural effusion and ascites. The original RECIST publication specifies that cytologic 
confirmation of the neoplastic nature of any effusion that appears or worsens during 
treatment is required when the measurable tumor has met criteria for response or stable 
disease. Under such circumstances, the cytologic examination of the fluid collected 
will permit differentiation between response or stable disease (an effusion may be a 
side effect of the treatment) and progressive disease (if the neoplastic origin of the fluid 
is confirmed). The mRECIST for HCC panel of experts considered this issue to be of 
high importance in the setting of HCC in cirrhosis. The emergence or the increase in 
ascites is a common event during the course of treatment in a cirrhotic patient, which 
may be due to worsening of the underlying chronic liver disease and be unrelated to 
cancer progression.45 Other effusions, such as pleural effusion, may also be unrelated 
to cancer progression and be caused by the liver insufficiency. Thus, the mRECIST for 
HCC emphasizes that cytopathologic confirmation of the neoplastic nature of any 
effusion (particularly ascites) that appears or worsens during treatment is required 
when the measurable tumor has met criteria for response or stable disease. It has to be 
underlined that peritoneal carcinomatosis is a very rare event in HCC. 
 
8.7.3 New Lesions 
Characterization of a newly detected focal liver lesion as true HCC is a challenging issue 
in the setting of cirrhosis because pathologic abnormalities related to cirrhosis changes—
such as large regenerative nodules and dysplastic nodules—may be indistinguishable from 
a small tumor. Moreover, the clear-cut separation of the hepatic phases of liver 
enhancement routinely achieved by state-of-the-art CT or MRI creates additional problems 
in a cirrhotic liver, mostly related to the presence of perfusion abnormalities resulting in 
areas of abnormal liver enhancement. In most cases, such perfusion abnormalities are 
detected as arterially hyperenhancing areas caused by a selective impairment of the portal 
venous feeding. Such perfusion abnormalities may ultimately mimic or conceal focal liver 
lesions; hence, they represent an additional major source for interpretation errors. 
 
The AASLD practice guideline for the clinical management of HCC has recommended 
strict criteria for the imaging diagnosis of HCC in cirrhosis.46 Noninvasive diagnostic 
criteria of HCC can be made without histology in lesions of at least 1 cm in diameter 
showing characteristic vascular features of HCC—arterial hypervascularization with 
washout in the portal venous or the late phase—at dynamic imaging studies. For diagnostic 
purposes, two imaging techniques—CT and MRI—are required for such a confirmation in 
tumors of 1 to 2 cm in diameter, and one imaging technique in tumors beyond 2 cm in 
cirrhotic patients. 
 


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In the assessment of tumor progression, these concepts have been adopted by the 
mRECIST assessment proposal, considering some specificities for the frame of 
progression mode (Fig. 2): 
 A newly detected hepatic nodule will be classified as HCC—and therefore will be 
declared as evidence of progression—when its longest diameter is at least 1 cm and the 
nodule shows the typical vascular pattern of HCC on dynamic imaging, that is, 
hypervascularization in the arterial phase with washout in the portal venous or late 
venous phase. 
 Liver lesions larger than 1 cm that do not show a typical vascular pattern can be 
diagnosed as HCC by evidence of at least 1-cm-interval growth in subsequent scans. 
 An individual radiologic event will be adjudicated in retrospect as progression at the 
time it was first detected by imaging techniques, even if strict criteria were fulfilled 
only on subsequent radiologic testing. 
 
 
Figure 2  Application of mRECIST assessment for hepatocellular carcinoma (HCC). New lesion. Computed tomography 
(CT) scans obtained in an HCC patient's follow‐up after treatment (main tumor not shown). On scans obtained at time 
point 1 (A, arterial phase; B, venous phase), a new lesion is identified (arrow). The tiny lesion is smaller than 1 cm; 
therefore, it must be considered equivocal. On CT scans obtained at time point 2 (C, arterial phase; D, venous phase), 
the tumor has become larger than 1 cm and shows the characteristic vascular pattern of HCC (arterial 
hypervascularization with venous washout). Although the criteria for diagnosing the lesion as HCC were fulfilled only at 
time point 2, progression must be declared in retrospect at time point 1, that is at the time the lesion was first 
detected. 
 


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8.8 
mRECIST: Overall Response Assessment 
In mRECIST for HCC, identical to conventional RECIST, overall subject response is a 
result of the combined assessment of target lesions, nontarget lesions, and new lesions 
(table below). It is important to point out that appearance of one or more new lesions 
declares progression whatever the response of target and nontarget lesions. Overcalling of 
equivocal lesions as new HCC, therefore, has a major impact on the outcome of studies 
with a radiologic endpoint, such as tumor response or time to progression. Hence, any 
newly detected focal liver lesion that does not meet the criteria reported above should be 
considered equivocal and not conclusive for disease progression. 
 
Overall Response Assessment in mRECIST: Responses for All Possible Combinations of Tumor 
Responses in Target and Nontarget Lesions with or without the Appearance of New Lesions 
Target Lesions 
Nontarget Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
IR/SD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or no 
PD 
Any 
PD 
Yes or no 
PD 
Any 
Any 
Yes 
PD 
mRECIST, modified Response Evaluation Criteria in Solid Tumors; CR, complete response; PR, partial 
response; IR, incomplete response; SD, stable disease; PD, progressive disease. 
 
 
9 
BIOLOGICAL CORRELATIVES  
 
Biological correlatives will be performed on Phase II subjects only. Refer to the Correlative 
Laboratory Manual associated with this protocol for collection, processing, labeling and shipping 
instructions of biological correlatives. 
 
An archived HCC tumor tissue block must be identified prior to registration. If an archived HCC 
tumor tissue block is not available, the patient must have a biopsy performed prior to registration 
to obtain HCC tumor tissue for correlative analysis. 
 
9.1 
Evaluate mTOR and PI3K/Akt expression and phosphoproteins via 
immunohistochemistry (IHC) of phosphorylated Akt, 4EBP1, S6 kinase, and ERK1/2. 
Immunohistochemical studies will be performed on unstained slides from an archived 
formalin-fixed/paraffin-embedded archival tumor tissue.  The presence of tumor tissue will 
be confirmed.. IHC will be performed per standardized protocols including the use of 
phospho-Akt (Ser473) (1:100, #4060, Cell SignalingTechnology), phospho-4EBP1 
(Thr37/46) (1:800, #2855, Cell Signaling Technology), phospho-S6 (Ser235/236) (1:50, 
#4858, Cell Signaling Technology) and phosphor-ERK1/2 (1:400, #4695, Cell Signaling 
Technology). Omission of the primary antibody will be used as a negative control along with 


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positive control tissue. Semi-automated quantitative brightfield assessment of expression 
will be performed using the Vectra imaging system (PerkinElmer) and inForm analysis 
software system. A scanning protocol will be generated based on the tissue size and location 
of the cancer within the sample. Biomarker quantification will be calculated as a continuous 
variable (mean optical density) and also as quartiles (ex. 0, 1+, 2+, or 3+).  Biomarker 
quantification will then be correlated with treatment response.  
 
In total, 10 unstained slides (FFPE) will be required for all biologic correlatives.  See also 
section 9.4 regarding additional tissue requirements for tissue banking for future studies. 
 
9.2 
Characterize oncogene expression affecting mTOR activation via targeted deep 
sequencing assay designed to interrogate genes commonly mutated in human cancers. 
Unstained slides from an archived formalin-fixed paraffin embedded archival tumor 
specimen for each subject will be obtained. The presence of tumor tissue will be confirmed.  
Pathology will guide isolation of DNA.  Genomic DNA will be prepared from an unstained 
slide using the Maxwell system as previously described by the manufacturer [Promega, 
Madison, WI] and stored. Typically, the amount of DNA extracted from tumor specimens 
range from 1000 to 5000ng from a single slide.  Targeted sequencing will be performed 
using the Ion AmpliSeq Cancer Panel® (Life Sciences). The Ion AmpliSeq Cancer Hotspot 
Panel v2 is designed to rapidly survey key cancer genes; including ABL1, AKT1, ALK, 
APC, ATM, BRAF, CDH1, CDKN2A, CSF1R, CTNNB1, EGFR, ERBB2, ERBB4, 
FBXW7, FGFR1-3, FLT3, GNAS, HNF1A, HRAS, IDH1, JAK2, JAK3, KDR, KIT, KRAS, 
MET, MLH1, MPL, NOTCH1, NPM1, NRAS, PDGFRA, PIK3CA, PTEN, PTPN11, RB1, 
RET, SMAD4, MARCB1, SMO, SRC, STK11, TP53, VHL for targeted mutations using the 
Ion Torrent PGM system and commercially available analysis software, such as NextGEN 
(Softgenetics, LLC). The mutation profiles of the tumors investigated will then be correlated 
with treatment response to TAK-228.  
 
In total, 10 unstained slides (FFPE) will be required for all biologic correlatives.  See also 
section 9.4 regarding additional tissue requirements for tissue banking for future studies.  
 
9.3 
Assess tumor necrosis and modified RECIST (mRECIST) criteria  
De-identified images will be stored centrally, and central image analysis performed 
including tumor necrosis and mRECIST quantification.  
 
9.4 
Samples for future studies 
Subject consent will be obtained for additional samples collected for future Big Ten Cancer 
Research Consortium studies. Hoosier Cancer Research Network, as Administrative 
Headquarters for the BTCRC, will manage the banked samples.  
 
 Central image analysis and storage of de-identified images. These central images will be 
stored at Northwestern for future use after the planned analysis for this trial. 
 
The following samples will be banked indefinitely in the Hoosier Cancer Research Network 
biorepository. 
 Whole blood:  
o Whole blood will be collected prior to treatment on Cycle 1 Day 1.  


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 Pre- and Post-treatment plasma:  
o Whole blood for plasma will be collected prior to treatment on Cycle 1 Day 1 and at 
End of Treatment.  
 Pre- and Post-treatment serum:  
o Whole blood for serum will be collected prior to treatment on Cycle 1 Day 1 and at 
End of Treatment. 
 Unstained slides:  
o Unstained slides will be obtained from the subject’s archived formalin fixed paraffin 
embedded tumor sample.  
 
Please refer to the Clinical Laboratory Manual for all sample collection, processing, 
labeling and shipping instructions. 
 
 
10 
DRUG INFORMATION  
 
10.1 TAK-228 
 
10.1.1 Classification 
TAK-228 selectively and potently inhibits mTOR kinase (the concentration inhibiting 50% 
of enzyme activity [IC50] is 1.1 nM), inhibits mTORC1/2 signaling, and prevents cellular 
proliferation. 
 
TAK-228 inhibited phosphorylation of downstream modulators of mTORC1and mTORC2 
in human U87 glioblastoma tumor xenograft models in mice and showed strong tumor 
growth inhibition (TGI) at tolerable oral (PO) doses in all 8 xenograft models tested. 
 
10.1.2 Mechanism of Action 
TAK-228 selectively and potently inhibits mTOR kinase (IC50 = 1.1 nM), inhibits 
mTORC1/2 signaling, and prevents cellular proliferation. The mTOR is a kinase that 
regulates cell growth, translational control, angiogenesis, and cell survival by integrating 
nutrient and hormonal signals. mTOR kinase plays a key role in several pathways that are 
frequently dysregulated in human cancer.36 mTORC1 is best known as a key regulator of 
protein translation through phosphorylation of 4EBP1 (the eukaryotic translation Initiation 
Factor 4E-binding Protein 1) and ribosomal protein S6 (known as S6) kinase. mTORC2 is 
best known for its ability to fully activate protein kinase B (Akt) by phosphorylation on the 
S473 site, which regulates proliferation and survival pathways.37 
 
10.1.3 Availability 
TAK-228 will be supplied by Millennium Pharmaceuticals as capsules for oral 
administration. The TAK-228 capsule contains milled active pharmaceutical ingredient 
(API). 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  
 
10.1.4 Storage, Handling and Accountability 
TAK-228 should be stored at controlled room temperature 15°C to 30°C (59°F to 86°F). 
All study supplies must be kept in a restricted access area. 
 
Because TAK-228 is an investigational agent, it should be handled with due care. In case 
of contact with broken capsules, raising dust should be avoided during the clean-up 
operation. The product may be harmful if inhaled, ingested, or absorbed through the skin. 
Gloves and protective clothing should be worn during the clean-up operation. The area 
should be ventilated and the spill site washed after material pick-up is complete. The 
spilled material should be disposed of as hazardous medical waste in compliance with 
federal, state, and local regulations. In case of contact with the powder (e.g., from a broken 
capsule), skin should be washed immediately with soap and copious amounts of water for 
at least 15 minutes. In case of contact with the eyes, copious amounts of water should be 
used to flush the eyes for at least 15 minutes. Medical personnel should be notified. 
Accountability for TAK-228 at all study sites is the responsibility of the sponsor-
investigator.  
 
10.1.5 Preparation, Reconstitution, and Dispensing 
TAK-228 study drug will be provided in 60 cc high-density polypropylene (HDPE) bottles 
with polypropylene, child-resistant caps and induction seal. Study drug will be dispensed 
with dosing instructions for home use, including the requirement that capsules are stored in 
their original containers and that capsules be swallowed whole and not opened, chewed, or 
manipulated in any way. Materials provided by the sponsor should be dispensed to subjects 
with clear administration instructions from the investigator. 
 
TAK-228 is an anticancer drug and, as with other potentially toxic compounds, caution 
should be exercised when handling TAK-228 capsules. 
 
Study drug will be administered or dispensed only to eligible subjects under the 
supervision of the investigator or identified sub-investigator(s). The appropriate study 
personnel will maintain records of study drug receipt and dispensing. 
 
10.1.6 Interactions with Other Medicaments and Other Forms of Interaction 
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. 
 


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10.1.7 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 MedComm Solutions (see below) and report the event. Whenever 
possible, the associated product should be maintained in accordance with the label 
instructions pending further guidance from a Millennium Quality representative. 
 
For Product Complaints, 
call MedComm Solutions at 
Phone: 1-866-VELCADE (1-866-835-2233) 
E-mail: GlobalOncologyMedinfo@takeda.com 
Millennium study number: IISR-2014-100530 (Bert O’Neil, MD) 
 
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 BTCRC Administrative Headquarters 
(See Section 11.3).  
 
10.1.8 Special Warnings and Special Precautions for Use 
 
Insulin and Glucose Levels 
Hyperglycemia and hyperinsulinemia are known toxicities associated with inhibition of 
mTOR (mechanistic [formerly mammalian] target of rapamycin) 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, as noted previously, have resulted in good control of glucose levels for the 
majority of TAK-228-treated subjects who developed hyperglycemia.  
 
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 
9December 2015, there has been 1 report of ventricular fibrillation and cardiac arrest post-
dose that had a fatal outcome and was assessed as related to TAK-228. Routine cardiac 
monitoring with baseline and on-study electrocardiograms (ECGs) and physical 
examination constitute the core cardiac safety monitoring in all TAK-228 studies. 
 


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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 (further 
details available in 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. 
 
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 intravenous (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. Subjects should be encouraged to drink at least 20 ounces of fluids a day, 
especially on days requiring fasting (per protocol), with administration of IV fluids in the 
clinic as indicated to avoid dehydration. 
 
Baseline macroscopic urinalysis and routine serum chemistries along with other safety 
laboratory assessments are performed in all 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, to further evaluate possible etiologies for the renal dysfunction. 
 
Rash 
Rash observed in clinical studies of TAK-228 tends to be maculopapular and pruritic and 
has ranged from Grade 1 to 3. For the most part, rash and pruritus improve with 
antihistamines, topical steroid creams, and/or dose interruption. Some subjects have 
required pulse systemic steroids, dose reduction, and/or study treatment discontinuation. 
 
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. 
 
Please reference the current TAK-228 Investigator’s Brochure for a complete list of 
adverse reactions. 
 


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10.2 Sorafenib 
 
10.2.1 Classification 
Kinase inhibitor (Raf, VEGFR, and PDGFR) 
 
10.2.2 Mechanism of Action 
Sorafenib is a kinase inhibitor that decreases tumor cell proliferation in vitro.  
 
Sorafenib was shown to inhibit multiple intracellular (c-CRAF, BRAF and mutant BRAF) 
and cell surface kinases (KIT, FLT-3, RET, RET/PTC, VEGFR-1, VEGFR-2, VEGFR-3, 
and PDGFR-ß). Several of these kinases are thought to be involved in tumor cell signaling, 
angiogenesis and apoptosis. Sorafenib inhibited tumor growth of HCC, RCC, and DTC 
human tumor xenografts in immunocompromised mice. Reductions in tumor angiogenesis 
were seen in models of HCC and RCC upon sorafenib treatment, and increases in tumor 
apoptosis were observed in models of HCC, RCC, and DTC. 
 
10.2.3 Availability 
Sorafenib tablets are supplied as round, biconvex, red film-coated tablets, debossed with 
the “Bayer cross” on one side and “200” on the other side, each containing sorafenib 
tosylate equivalent to 200 mg of sorafenib. 
 
Commercial supplies of sorafenib will be used in this study and billed to third party payers 
or the subject.  
 
10.2.4 Storage 
Store at 25° C (77° F); excursions permitted to 15–30° C (59–86° F) (see USP controlled 
room temperature). Store in a dry place. 
 
10.2.5 Administration 
Following oral administration, sorafenib’s mean relative bioavailability is 38-49%. When 
given with a moderate fat meal, bioavailability was similar to that in the fasted state. With 
a high fat meal, sorafenib’s bioavailability was reduced by 29% compared to 
administration in the fasted state. Thus, it is recommended that sorafenib be taken on an 
empty stomach (at least 1 hour before or 2 hours after eating) and with at least 250 mL of 
water. 
 
10.2.6 Drug Interactions 
Sorafenib is neither a clinically meaningful inhibitor nor a clinically meaningful inducer of 
CYP2C19, CYP2D6, and CYP3A4 isoenzymes and is not expected to significantly 
increase or decrease the exposure of co-administered compounds metabolized by these 
pathways. However, concomitant administration of sorafenib and CYP3A4 inducers, such 
as phenytoin, carbamazepine, phenobarbital, rifampin, or St. John’s wort, should be 
avoided. Co-administration with doxorubicin or docetaxel leads to a moderate increases in 
doxorubicin exposure and docetaxel AUC, respectively. Co-administration with irinotecan 
leads to a significant increase in SN-38 (i.e., the active metabolite of sorafenib, which is 
eliminated by UGT1A9) exposure. 
 


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10.2.7 Side Effects 
The following additional drug-related adverse reactions and laboratory abnormalities were 
reported from clinical trials of sorafenib (very common 10% or greater, common 1 to less 
than 10%, uncommon 0.1% to less than 1%): 
Cardiovascular: Common: congestive heart failure*†, myocardial ischemia and/or 
infarction Uncommon: hypertensive crisis* Rare: QT prolongation* 
Dermatologic: Very common: erythema Common: exfoliative dermatitis, acne, flushing 
Uncommon: folliculitis, eczema, erythema multiforme, keratoacanthomas/squamous cell 
cancer of the skin 
Digestive: Very common: increased lipase, increased amylase Common: mucositis, 
stomatitis (including dry mouth and glossodynia), dyspepsia, dysphagia Uncommon: 
pancreatitis, gastrointestinal reflux, gastritis, gastrointestinal perforations*, cholecystitis, 
cholangitis 
Note that elevations in lipase are very common (41%, see below); a diagnosis of 
pancreatitis should not be made solely on the basis of abnormal laboratory values 
General Disorders: Very common: hemorrhage (including gastrointestinal* & respiratory 
tract* and uncommon cases of cerebral hemorrhage*), asthenia, pain (including mouth, 
bone, and tumor pain) Common: decreased appetite, influenza-like illness, pyrexia 
Uncommon: infection 
Hematologic: Very common: leukopenia, lymphopenia Common: anemia, neutropenia, 
thrombocytopenia Uncommon: INR abnormal 
Hypersensitivity: Uncommon: hypersensitivity reactions (including skin reactions and 
urticaria) 
Metabolic and Nutritional: Very common: hypophosphatemia Common: transient 
increases in transaminases, hypocalcemia, hypokalemia Uncommon: dehydration, 
hyponatremia, transient increases in alkaline phosphatase, increased bilirubin (including 
jaundice), hypothyroidism, hyperthyroidism 
Musculoskeletal: Common: arthralgia, myalgia 
Nervous System and Psychiatric: Common: depression Uncommon: tinnitus, reversible 
posterior leukoencephalopathy* 
Renal and Genitourinary: Common: renal failure, proteinuria Rare: Nephrotic syndrome 
Reproductive: Common: erectile dysfunction Uncommon: gynecomastia 
Respiratory: Common: hoarseness Uncommon: rhinorrhea, interstitial lung disease-like 
events (includes reports of pneumonitis, radiation pneumonitis, acute respiratory distress, 
interstitial pneumonia, pulmonitis and lung inflammation) 
In addition, the following medically significant adverse reactions were uncommon during 
clinical trials of sorafenib: transient ischemic attack, arrhythmia, and thromboembolism. 
For these adverse reactions, the causal relationship to sorafenib has not been established. 
*adverse reactions may have a life-threatening or fatal outcome. 
†reported in 1.9% of subjects treated with sorafenib (N= 2276). 


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10.2.8 Warnings and Precautions 
 
Risk of Cardiac Ischemia and/or Infarction 
In the HCC study, the incidence of cardiac ischemia/infarction was 2.7% in sorafenib-
treated subjects compared with 1.3% in the placebo-treated group and in RCC Study 1, the 
incidence of cardiac ischemia/infarction was higher in the sorafenib-treated group (2.9%) 
compared with the placebo-treated group (0.4%). Subjects with unstable coronary artery 
disease or recent myocardial infarction were excluded from this study. Temporary or 
permanent discontinuation of sorafenib should be considered in subjects who develop 
cardiac ischemia and/or infarction. 
 
Risk of Hemorrhage 
An increased risk of bleeding may occur following sorafenib administration. In the HCC 
study, an excess of bleeding regardless of causality was not apparent and the rate of 
bleeding from esophageal varices was 2.4% in sorafenib-treated subjects and 4% in 
placebo-treated subjects. Bleeding with a fatal outcome from any site was reported in 2.4% 
of sorafenib-treated subjects and 4% in placebo-treated subjects. In RCC Study 1, bleeding 
regardless of causality was reported in 15.3% of subjects in the sorafenib-treated group and 
8.2% of subjects in the placebo-treated group. The incidence of CTCAE Grade 3 and 4 
bleeding was 2% and 0%, respectively, in sorafenib-treated subjects, and 1.3% and 0.2%, 
respectively, in placebo-treated subjects. There was one fatal hemorrhage in each treatment 
group in RCC Study 1. If any bleeding necessitates medical intervention, permanent 
discontinuation of sorafenib should be considered. 
 
Risk of Hypertension 
Monitor blood pressure weekly during the first 6 weeks of sorafenib, in accordance with 
standard medical practice. Thereafter, monitor blood pressure and treat hypertension, if 
required, in accordance with standard medical practice. In the HCC study, hypertension 
was reported in approximately 9.4% of sorafenib-treated subjects and 4.3% of subjects in 
the placebo-treated group. In RCC Study 1, hypertension was reported in approximately 
16.9% of sorafenib-treated subjects and 1.8% of subjects in the placebo-treated group. 
Hypertension was usually mild to moderate, occurred early in the course of treatment, and 
was managed with standard antihypertensive therapy. In cases of severe or persistent 
hypertension despite institution of antihypertensive therapy, consider temporary or 
permanent discontinuation of sorafenib. Permanent discontinuation due to hypertension 
occurred in 1 of 297 sorafenib-treated subjects in the HCC study and 1 of 451 sorafenib-
treated subjects in RCC Study 1. 
 
Risk of Dermatologic Toxicities 
Hand-foot skin reaction and rash represent the most common adverse reactions attributed 
to sorafenib. Rash and hand-foot skin reaction are usually CTCAE Grade 1 and 2 and 
generally appear during the first six weeks of treatment with sorafenib. Management of 
dermatologic toxicities may include topical therapies for symptomatic relief, temporary 
treatment interruption, and/or dose modification of sorafenib, or in severe or persistent 
cases, permanent discontinuation of sorafenib. Permanent discontinuation of therapy due to 


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hand-foot skin reaction occurred in 4 of 297 sorafenib-treated subjects with HCC and 3 of 
451 sorafenib-treated subjects with RCC. 
There have been reports of severe dermatologic toxicities, including Stevens-Johnson 
syndrome (SJS) and toxic epidermal necrolysis (TEN). These cases may be life 
threatening. Discontinue sorafenib if SJS or TEN are suspected. 
 
Risk of Gastrointestinal Perforation 
Gastrointestinal perforation is an uncommon adverse reaction and has been reported in less 
than 1% of patients taking sorafenib. In some cases, this was not associated with apparent 
intra-abdominal tumor. In the event of a gastrointestinal perforation, discontinue sorafenib. 
 
Warfarin 
Infrequent bleeding or elevations in the International Normalized Ratio (INR) have been 
reported in some patients taking warfarin while on sorafenib. Monitor subjects taking 
concomitant warfarin regularly for changes in prothrombin time (PT), INR, or clinical 
bleeding episodes. 
 
Wound Healing Complications 
No formal studies of the effect of sorafenib on wound healing have been conducted. 
Temporary interruption of sorafenib is recommended in subjects undergoing major 
surgical procedures. There is limited clinical experience regarding the timing of reinitiation 
of sorafenib following major surgical intervention. Therefore, the decision to resume 
sorafenib following a major surgical intervention should be based on clinical judgment of 
adequate wound healing. 
 
Please reference the current US prescribing information for a complete list of 
sorafenib adverse reactions. 
 
10.2.9 Nursing Considerations 
 Monitor for jaundice.  
 Evaluate subject for GI intolerance.  
 Sorafenib should be taken on an empty stomach (at least 1 hour before or 2 hours after 
eating) and with at least 250 mL of water. 
 
 
11 
ADVERSE EVENTS  
 
11.1 Definitions 
 
11.1.1 Adverse Event (AE): 
Any untoward medical occurrence in a subject administered an investigational product and 
which does not necessarily have a causal relationship with the treatment. An adverse event 
(AE) can therefore be any unfavorable and unintended sign (including an abnormal 
finding), symptom, or disease temporally associated with the use of an investigational 
product, whether or not related to the investigational 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. 
 
11.1.2 Serious Adverse Event (SAE): 
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 (eg, prion protein transmitting Transmissible 
Spongiform Encephalopathy), pathogenic or nonpathogenic, is considered an infectious 
agent.   
 
Serious vs. Severe: 
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 subject/event 
outcome or action criteria described above, and is usually associated with events that pose 
a threat to a subject’s life or ability to function. A severe AE (Grade 3 or 4) does not 
necessarily need to be considered serious. For example, a white blood cell count of 
1000/mm3 to less than 2000 is considered Grade 3 (severe) but may not be considered 
serious. Seriousness (not intensity) serves as a guide for defining regulatory reporting 
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11.1.3 Unexpected Adverse Event: 
An adverse event not mentioned in the Investigator's Brochure or package insert or the 
specificity or severity of which is not consistent with the Investigator's Brochure or 
package insert. 
 
11.1.4 Causality 
AEs will be categorized according to the likelihood that they are related to the study 
drug(s). Specifically, they will be categorized using the following terms: 
Unrelated 
The Adverse Event is clearly not related to the study drug(s) 
Unlikely 
The Adverse Event is doubtfully related to the study drug(s) 
Possible 
The Adverse Event  may be related to the study drug(s) 
Probable 
The Adverse Event is likely related to the study drug(s) 
Definite 
The Adverse Event is clearly related to the study drug(s) 
 
11.2 Reporting 
 
AEs may be spontaneously reported by the subject 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 (AEs) will be recorded from the time of consent and for at least 30 days after 
treatment discontinuation, regardless of whether or not the event(s) are considered related to trial 
medications.  
 
All AEs considered related to study drug(s) will be followed until resolution, return to baseline, or 
deemed clinically insignificant, even if this occurs post-trial. 
11.3 Serious Adverse Event (SAE) Reporting 
 
11.3.1 Site Requirements for Reporting SAEs to BTCRC AHQ: 
Adverse Events which are serious must be reported from the initiation of study drug(s) and 
for 30 days after administration of the last dose of study drug(s). Any SAE that occurs at 
any time after treatment discontinuation or after the designated follow-up period that the 
site investigator and/or sub-investigator considers to be related to any study drug must be 
reported. Planned hospital admissions or surgical procedures for an illness or disease that 
existed before the subject was enrolled in the trial are not to be considered SAEs unless the 
condition deteriorated in an unexpected manner during the trial (e.g., surgery was 
performed earlier or later than planned). Deaths due to unequivocal progression are not 
SAEs. All SAEs should be monitored until they are resolved or are clearly determined to 
be due to a subject’s stable or chronic condition or intercurrent illness(es). 
 


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Investigators and other site personnel must report any SAE within one business day of 
discovery of the event. This includes events both related and unrelated to the 
investigational product.  
 
The completed SAE Submission Form (see SPM) must be faxed (317-921-2053) or e-
mailed (SAFETY@hoosiercancer.org) to Big Ten Cancer Research Consortium 
(BTCRC) Administrative Headquarters (AHQ) within one business day of discovery 
of the event. The investigator is responsible for informing the IRB and/or the Regulatory 
Authority of the SAE as per local requirements. 
 
The SAE report must include at minimum: 
o Event term(s) 
o Serious criteria 
o Intensity of the event(s): site 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. 
o Causality of the event(s): site investigator’s or sub-investigator’s determination of the 
relationship of the event(s) to study drug administration. Relationship to all study drugs 
for each SAE will be determined by the site 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)? 
 
A copy of the SAE Submission Form can be found in the Study Procedures Manual 
(SPM).The original SAE report along with e-mail correspondence and/or the fax 
confirmation sheet must be kept within the study file at the study site. 
 
SAE follow-up information must be submitted via e-mail or faxed to BTCRC AHQ, using 
the SAE Submission Form. Each re-occurrence, complication, or progression of the 
original event should be reported as a follow-up to that event regardless of when it occurs. 
The follow-up information should describe whether the event has resolved or continues, if 
and how it was treated, whether the blind was broken or not (if applicable), and whether 
the subject continued or withdrew from study participation. 
 
11.3.2 Site Procedures for Reporting Drug Exposure during Pregnancy and Birth Events to 
BTCRC AHQ 
If a female subject becomes pregnant or suspects that she is pregnant while participating in 
this study (i.e. from the initiation of study drug(s) through 90 days after the last dose of 
study drug), she must inform the investigator immediately and permanently discontinue 
study drug. The site investigator must fax a completed Clinical Pregnancy Report (see 
SPM) to BTCRC AHQ within 1 business day. BTCRC AHQ will submit the form to the 
Millennium Department of Pharmacovigilance or designee. The pregnancy must be 
followed for the final pregnancy outcome. 
 
If a female partner of a male subject becomes pregnant during the male subject’s 
participation in this study (i.e. from the initiation of study drug(s) through 120 days after 
the last dose of study drug), the site investigator must also immediately fax a completed 


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Clinical Pregnancy Report to BTCRC AHQ within 1 business day. BTCRC AHQ will 
submit the form to the Millennium Department of Pharmacovigilance or designee. Every 
effort should be made to follow the pregnancy for the final pregnancy outcome. 
 
11.3.3 BTCRC AHQ Requirements for Reporting SAEs to Millennium Pharmacovigilance: 
BTCRC AHQ will report all SAEs, regardless of expectedness or causality, to Millennium 
Pharmacovigilance.  
 Fatal and Life Threatening SAEs: within 1 business day of awareness of the event.  
 All other serious (non-fatal/non-life threatening) events: within 4 calendar days of 
awareness of the event. See below for contact information for the reporting of SAEs 
to Millennium Pharmacovigilance.  
Since this is a multisite study, the sponsor-investigator has delegated responsibility to 
BTCRC AHQ to ensure that the SAE reports are sent to Millennium Pharmacovigilance 
(or designee) from all sites participating in the study. Site investigators must centrally 
report all SAEs to BTCRC AHQ so that the sponsor-investigator can meet his/her 
foregoing reporting obligations to the required regulatory agencies and to Millennium 
Pharmacovigilance.  
 
 
SAE and Pregnancy Reporting Contact Information 
 
US and Canada 
Fax Number: 1-800-963-6290 
Email: TakedaOncoCases@cognizant.com 
 
BTCRC AHQ will fax or email the SAE Submission Form or MedWatch to Cognizant and 
will provide follow-up information as reasonably requested. 
 
11.4 BTCRC AHQ Requirements for Reporting SAEs to FDA 
BTCRC AHQ has been designated to manage the Investigational New Drug Application (IND) 
associated with this protocol on behalf of Bert O’Neil, M.D., sponsor-investigator.  BTCRC AHQ 
will cross-reference this submission to Millennium/ Takeda’s parent IND at the time of 
submission. Additionally, HCRN will submit a copy of these reports to Millennium/ Takeda at the 
time of submission to FDA. 
 
BTCRC AHQ will report to the FDA any AE that is serious, unexpected and reasonably related 
(i.e., possible, probably, definite) to the study treatment. 
 
7-day Reporting: 
According to CFR 312.32, unexpected fatal or life-threatening events possibly related with the use 
of the study drug (drugs) will be reported to the FDA by fax or by phone as soon as possible, but 
in no event later than 7 calendar days after the initial receipt of the information regarding the 
event. The fax should be sent to the FDA project manager assigned to the IND. A comprehensive 


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written report will be submitted as an amendment to the IND within an additional 8 days (15 
calendar days total).   
 
15-day Reporting: 
All other serious unexpected events associated with the use of the study drug will be reported to 
FDA as an amendment to the IND as soon as possible, but in no event later than 15 calendar days 
after initial receipt of the information regarding the event.  
 
BTCRC AHQ will be responsible for all communication with the FDA including but not limited to 
the 7 and 15 Day Reports, as well as an Annual Progress Report. Additionally, BTCRC AHQ will 
submit a copy of these reports to Millennium Pharmacovigilance at the time of submission to 
FDA. 
 
11.5 IND Safety Reports Unrelated to This Trial 
Millennium Pharmacovigilance will send IND safety reports not occurring on this trial but 
involving the study intervention (outside SAEs) to BTCRC AHQ (SAFETY@hoosiercancer.org). 
BTCRC AHQ will forward the safety reports to the sponsor-investigator who will review the 
reports and determine if any revisions are needed to the protocol or consent. BTCRC AHQ will 
make the reports available to participating sites via OnCore.  
 
Upon receipt from BTCRC AHQ, site investigators (or designees) are responsible for submitting 
the safety reports to their Institutional Review Boards per their local guidelines.  
 
 
12 
STATISTICAL CONSIDERATIONS 
 
12.1 General Considerations 
 
Statistical analysis of this study will be the responsibility of Biostatistics and Data Management 
Core at Indiana University Melvin and Bren Simon Cancer Center (IUSCC). Parameter estimates 
and relevant summary statistics will be reported where appropriate. For continuous variables, 
summary statistics will include number of subjects, mean, median, standard deviation, minimum 
and maximum. Categorical endpoints will be summarized using number of subjects, frequency, 
and percentages. Missing data will not be imputed. Data analysis will be performed in SAS 
Version 9.3. 
 
Additional exploratory analyses of the data will be conducted as deemed appropriate. Changes 
from this analysis plan will not require an amendment to the protocol unless it changes a 
significant feature of the protocol. 
 
12.2 Study Design 
 
This will be an open-label Phase I/II study.  Phase I is a traditional 3+3 design with three dose 
levels (15, 20, and 30 mg QW). See Section 5.4.2 for specific details. This will be followed by a 
randomized phase II clinical trial. Eligible subjects will be 1:1 randomized to either TAK-228 or 
sorafenib. Block randomization stratified by CP score (5-6 vs. 7) will be adopted with varying 
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12.3 Analysis Datasets 
 
Population 
Definition 
Enrolled 
This will comprise all subjects who meet the eligibility 
criteria and are registered onto the study.  
Efficacy 
This will comprise all subjects who have a baseline disease 
evaluation, have received at least one dose of study drug 
and have had at least one post-baseline disease evaluation. 
All subjects will be analyzed in the group to which they 
were randomized, regardless of which treatment was 
administered.  
Safety 
This will comprise all subjects who received at least 1 dose of 
study drug.  
Pharmacokinetic 
This will comprise the first 10 subjects in TAK-228 study arm 
who will undergo PK data collection. 
 
12.4 Sample Size/Accrual/Study Duration/Replacement Rules  
 
The sample size for Phase I will depend on the DLTs observed and could range from 3 to 18. 
 
For the Phase II study, therapy with sorafenib in subjects with CPA cirrhosis was associated with a 
median TTP of 5.5 months. Given inclusion of CP 7 subjects (technically CPB), we would 
anticipate a median TTP of 12-week for sorafenib. In this Phase II study, we assume that TAK-
228 will increase TTP from 50% to 70% at week 12. A 10% dropout rate is expected for the 
sorafenib arm and a similar dropout pattern is expected for the TAK-228 arm. Enrollment is 
expected to be completed in 24 months. Subjects will be followed for a total of 2 years after 
progression. Two-sided log-rank test will be used to compare TTP at type I error level 0.05. 
Consequently, N=44 subjects per group are required to obtain a power level of 0.80. Subjects not 
evaluable for response will be replaced, so we further adjust the sample size to N=50 per group to 
account for potentially unevaluable subjects. 
 
The expected accrual rate is 5 subjects/month. The accrual is based on an initial estimate reflecting 
accrual of previous phase II studies in HCC conducted by different groups, and upon the 
participation of additional groups within the BTCRC. Total expected accrual is 88 minimum, and 
100 maximum. We do not expect any differences in accrual compared to historical controls.  
 
12.5 Subject Characteristics and Significant Protocol Violations 
 
Subject demographics and subject baseline characteristics will be listed and summarized for all 
subjects enrolled, including age, gender, and race by phase. Counts, means, medians, standard 
deviation, minimum and maximum values will be presented. For Phase II, the treatment groups 
will be compared using either Student’s t-test or Pearson’s chi-square test. Significant protocol 
violations will be listed. 
 


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12.6 Concomitant Medication 
 
Concomitant medication use will be tabulated by phase and by treatment group for Phase II. 
 
12.7 Disposition 
 
Subject disposition will be tabulated by phase and treatment group for Phase II and will show the 
number of subjects enrolled, and the number of subjects completing the study. All reasons for 
discontinuation will be listed and summarized. 
 
12.8 Exposure/Compliance  
 
Pill counts/missed doses will be obtained at each visit in order to assess compliance. Cumulative 
dose will be calculated for each subject and descriptive statistics will be presented by phase and 
treatment group for Phase II. 
 
12.9 Analysis of Primary Objectives/Aims 
  
This will be done in the Efficacy population following the intent-to-treat principle (analyze as 
randomized). The primary objective in the Phase I cohort is to determine the maximum tolerated 
dose, and the primary objective in the Phase II cohort is time to progression (TTP). For Phase I, 
we will count the number of subjects and DLTs per dose cohort.  For the Phase II cohort, Kaplan-
Meier curves will be plotted for each treatment group. Median TTP times will be computed, and 
TTP rate at 4 months +/- 1 week will be calculated with associated 95% confidence intervals. 
Survival curves will be compared using the log-rank test.  
 
12.10 Analysis of Secondary Objectives/Aims 
 
Phase I:   
All analyses of secondary objectives will be by listings/tabulations only and reported by dose 
cohort. 
 
Phase II: 
OS and PFS will be analyzed similarly to the primary outcome. For OS, Cox regression will be 
used to evaluate the effects of oncogenic abnormalities on survival times.  
 
Preliminary information will be collected for treatment related toxicity and tolerance in the safety 
population. Toxicity will be graded using the NCI’s Common Terminology Criteria for Adverse 
Events version 4 (CTCAE v4). Treatment tolerance will be based on the number of treatment 
delays and dose reductions. Information will be presented in a tabular and descriptive manner. 
Proportion of subjects with each grade of toxicity will be computed along with 95% confidence 
intervals, and reported in a tabular and descriptive manner. Toxicity will be compared by 
treatment group using chi-square or Fisher’s exact tests.  
 
Objective Response rate (ORR) and Disease control rate (DCR) will be estimated by proportions 
with 95% confidence intervals by treatment group and reported graphically via waterfall plot. 
 


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12.11 Tertiary/Exploratory/Correlative Endpoints (Phase II subjects only) 
 
Pharmacokinetics 
Pharmacokinetics (PK) will be evaluated in first 10 subjects in TAK-228 arm at predose, 0.5, 1, 2, 
4, 6, 8, and 24 hours on C1D1 and C2D1. An exploratory analysis will be assessed and correlated 
with clinical outcomes. The pharmacokinetic parameters for TAK-228 will be expressed by 
descriptive statistics (geometric mean, median, standard deviation, and coefficient of variation). 
The primary pharmacokinetic parameters investigated for each compound will be AUC0-t, AUC0-∞, 
Cmax and λz. Descriptive statistics will be calculated for the demographic data. Graphs and Pearson 
or Spearman correlations will be used to examine the distribution of values and bivariate 
relationships. 
 
Evaluate mTOR and PI3K/Akt expression and phosphoproteins via immunohistochemistry 
(IHC) of phosphorylated Akt, 4EBP1, S6 kinase, and ERK1/2. 
Immunohistochemical studies will be performed on formalin-fixed/paraffin-embedded archival 
tumor tissue.  Biomarker quantification will be calculated as a continuous variable (mean optical 
density) and also as quartiles (ex. 0, 1+, 2+, or 3+).  Biomarker quantification will then be 
correlated with treatment response. All correlative studies are considered exploratory.  Descriptive 
statistics will primarily be generated to summarize the above data.  For continuous variables, 
descriptive statistics may include the number of subjects (n), mean, standard deviation, median, 
minimum, and maximum; frequencies and percentages may be displayed for categorical data.  
Data summaries will be presented by experimental cohort.  Statistical significance will be 
determined by students t-test for normally distributed data. If data distributions are not normal, a 
non-parametic test will be used (Wilcoxon rank sum test). 
 
Characterize oncogene expression affecting mTOR activation via targeted deep sequencing 
assay designed to interrogate genes commonly mutated in human cancers. 
Formalin-fixed paraffin embedded archival tumor specimens for each subject will be obtained. The 
presence of tumor tissue will be confirmed by a central surgical pathologist.  Targeted sequencing 
will be performed using the Ion AmpliSeq Cancer Panel® (Life Sciences). The Ion AmpliSeq Cancer 
Hotspot Panel v2 is designed to rapidly survey key cancer genes for targeted mutations using the 
Ion Torrent PGM system and commercially available analysis software, such as NextGEN 
(Softgenetics, LLC). The mutation profiles of the tumors investigated will then be correlated with 
treatment response to TAK-228. Descriptive statistics will be used to summarize the data and a 
logistic regression will be performed to correlate mutation prolife to treatment response. 
 
Assess tumor necrosis and modified RECIST (mRECIST) criteria. 
De-identified images will be sent to Northwestern’s Quantitative Imaging Core Lab for analysis.  
Three imaging time points will be collected: baseline, at best response, at upon progression of 
disease.  Images will be stored centrally, and image analysis performed including tumor necrosis 
and modified RECIST (mRECIST) criteria. Percent necrosis will be describe graphically and by 
mean, SD, median, minimum and maximum.  Frequency of response per mRECIST will tabulated. 
 
12.12 Interim Analysis 
 
No formal interim analyses are planned. 


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13 
TRIAL MANAGEMENT 
 
13.1 Quality Controls and Quality Assurance 
 
13.1.1 Study Monitoring: 
 
BTCRC AHQ staff will conduct at least one routine on-site monitoring visit per year per 
accruing trial site during the trial to ensure all aspects of the protocol are followed. Source 
documents will be reviewed for verification of agreement with data entered into OnCore. 
The investigator/ institution guarantee access to source documents by BTCRC AHQ or its 
designee and appropriate regulatory agencies. 
 
It is important for the site investigator and their relevant personnel to be available during 
the monitoring visits and possible audits and for sufficient time to be devoted to the 
process.  
 
The trial site may also be subject to quality assurance audit by Millennium 
Pharmaceuticals or its designee as well as inspection by appropriate regulatory agencies. 
 
13.1.2 Data and Safety Monitoring Plan: 
 
The study will be conducted in accord with the Indiana University Simon Cancer Center’s 
DSMP, and the Indiana University Simon Cancer Center’s Data and Safety Monitoring 
Committee (DSMC).   
 
BTCRC AHQ facilitated oversight activities include: 
 
Review and processing of all adverse events requiring expedited reporting as 
defined in the protocol 
 
Provide trial accrual progress, safety information, and data summary reports to the 
sponsor-investigator 
 
Notify participating sites of adverse events potentially requiring expedited 
reporting and subsequent DSMC recommendations for study modifications 
 
Investigators will conduct continuous review of data and patient safety.  
 
BTCRC AHQ will coordinate weekly review meetings for the phase I portion of the 
trial and then monthly meetings during the phase II portion. These meetings will 
include each accruing site’s principal investigator, clinical research specialist and/or 
research nurse (other members per principal investigator’s discretion).  
 
Meeting summaries from the above meetings should include review of data, the 
number of patients, significant toxicities as described in the protocol, SAEs, and 
responses observed. Summaries will be submitted and reviewed monthly by the 
DSMC. Submit to DSMC@iupui.edu. 
 
Submit data summary reports to the lead institution Data Safety Monitoring 
Committee according to IUSCC DSMP. 
 
13.1.3 IUSCC Data Safety Monitoring Committee (DSMC) and Protocol Progress 
Committee (PPC) 
The DSMC will review the following: 


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 Adverse event and serious adverse event summary report 
 Site monitoring and/or audit reports, if applicable 
 Data related to stopping/decision rules described in study design 
 Study accrual patterns  
 Protocol deviations 
 
The IUSCC DSMC will review the above data semi-annually during the phase I portion of the trial 
and then annually during the phase II portion.  Documentation of DSMC reviews will be provided 
to sponsor-investigator and HCRN.  Issues of immediate concern by the DSMC will be brought to 
the attention of the sponsor-investigator and other regulatory bodies as appropriate.  The sponsor-
investigator will work with HCRN to address the DSMC’s concerns.   
 
Additionally, monthly meeting summaries, including SAE and deviation reports, will be reviewed 
by the DSMC chair and/or coordinator monthly. Findings will be reported to the full DSMC at the 
time of study review.  Furthermore, the monthly meeting summaries will be available for the 
Protocol Progress Committee (PPC) who reviews study accrual twice per year while the PPC 
coordinator reviews accrual quarterly.  
 
At any time during the conduct of the trial, if it is the opinion of the investigators that the risks (or 
benefits) to the patient warrant early closure of the study, this recommendation should be made in 
writing to the Data Safety Monitoring Committee. Alternatively, the DSMC may initiate 
suspension or early closure of the study based on its review of the investigator reports.  
 
13.2 Data Handling and Record Keeping 
 
13.2.1 Data Management 
This study will utilize electronic case report forms (eCRFs) in the OnCore® database.  The 
OnCore® database is a comprehensive database used by BTCRC AHQ and properly used is 
compliant with Title 21 CFR Part 11.  Access to the data through OnCore® is restricted by 
user accounts and assigned roles.  Once logged into the OnCore® system with a user ID 
and password, OnCore® defines roles for each user, which limits access to appropriate data.  
User information and passwords can be obtained by contacting BTCRC AHQ at 317-921-
2050.   
 
13.2.2 Case Report Forms and Submission 
Generally, clinical data will be electronically captured in OnCore® and correlative results 
will be captured in OnCore® or other secure database. If procedures on the study calendar 
are performed for standard of care, at minimum, that data will be captured in the source 
document. Select standard of care data will also be captured in OnCore®, according to 
study-specific objectives. Please see the eCRF completion guidelines for further details.  
 
The completed dataset is housed at BTCRC AHQ and is the sole property of the sponsor-
investigator’s institution. It should not be made available in any form to third parties, 
except for authorized representatives of appropriate Health/Regulatory Authorities, without 
written permission from the sponsor-investigator and BTCRC AHQ. After the initial 
publication, the complete data set will be available to all BTCRC institutions. 
 


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13.2.3 Record Retention: 
To enable evaluations and/or audits from Health Authorities/BTCRC AHQ, the site 
investigator agrees to keep records, including the identity of all participating subjects 
(sufficient information to link records; e.g., hospital records), all original signed informed 
consent forms, copies of all source documents, and detailed records of drug disposition. 
All source documents are to remain in the subject’s file and retained by the investigator in 
compliance with local and federal regulations. 
 
During data entry, range and missing data checks will be performed on-line. The checks to 
be performed will be documented in the Data Monitoring Plan for the study. A summary 
report (QC Report) of these checks together with any queries resulting from manual review 
of the eCRFs will be generated for each site and transmitted to the site and the site 
monitor. Corrections will be made by the study site personnel. This will be done on an 
ongoing basis. 
 
13.3 Confidentiality 
There is a slight risk of loss of confidentiality of subject information.  All records identifying the 
subject will be kept confidential and, to the extent permitted by the applicable laws and/or 
regulations, will not be made publicly available. Information collected will be maintained on 
secure, password protected electronic systems. Paper files that contain personal information will 
be kept in locked and secure locations only accessible to the study site personnel.  
 
Samples that are collected will be identified by a subject study number assigned at the time of 
registration to the trial.  Any material issued to collaborating researchers will be anonymized and 
only identified by the subject study number. 
 
Subjects will be informed in writing that some organizations including the sponsor-investigator 
and his/her research associates, BTCRC AHQ, Millennium Pharmaceuticals, IRB, or government 
agencies, like the FDA, may inspect their medical records to verify the information collected, and 
that all personal information made available for inspection will be handled in strictest confidence 
and in accordance with local data protection laws. 
 
If the results of the study are published, the subject’s identity will remain confidential. 
 
13.4 Changes to the Protocol and Informed Consent 
Study procedures will not be changed without the mutual agreement of the sponsor-investigator, 
BTCRC AHQ, and Millennium Pharmaceuticals. 
 
If it is necessary for the study protocol and/or the informed consent to be amended, the 
amendment or a new version of the study protocol (amended protocol) will be generated by 
BTCRC AHQ and must be approved by the sponsor-investigator, Millennium Pharmaceuticals, 
the FDA (if applicable) and each site’s IRB. Local requirements must be followed. 
 
The site investigator is responsible for the distribution of these documents to his or her IRB, and to 
the staff at his or her center.  


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Millennium Pharmaceutical’s willingness to supply study drug is predicated upon the review of 
the protocol. BTCRC AHQ agrees to provide written notice to Millennium of any modifications to 
the protocol or informed consent. 
 
13.5 Ethics 
 
13.5.1 Institutional Review Board (IRB) Review: 
The final study protocol, including the final version of the Written Informed Consent 
Form, must be approved or given a favorable opinion in writing by an IRB. The 
investigator must submit written approval to the BTCRC AHQ office before he or she can 
enroll any subject into the study.  
 
The site investigator is responsible for informing the IRB of any amendment to the 
protocol in accordance with local requirements. In addition, the IRB must approve all 
advertising used to recruit subjects for the study. The protocol must be re-approved by the 
IRB, as local regulations require.  
 
Progress reports and notifications of adverse events will be provided to the IRB according 
to local regulations and guidelines. 
 
13.5.2 Ethical Conduct of the Study: 
The study will be performed in accordance with ethical principles originating from the 
Declaration of Helsinki, which are consistent with ICH Good Clinical Practice, and 
applicable regulatory requirements. 
 
13.5.3 Written Informed Consent: 
The site investigator will ensure the subject is given full and adequate oral and written 
information about the nature, purpose, possible risks and benefits of the study. Subjects 
must also be notified they are free to discontinue from the study at any time. The subject 
should be given the opportunity to ask questions and allowed time to consider the 
information provided. 
 
The subject’s signed and dated informed consent must be obtained before conducting any 
procedure specifically for the study. The investigator must store the original, signed 
Written Informed Consent Form. A copy of the signed Written Informed Consent Form 
must be given to the subject. 
 
13.5.4 Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and 
the Food and Drug Administration Amendments Act (FDAAA), the sponsor-investigator 
of the trial is solely responsible for determining whether the trial and its results are subject 
to the requirements for submission to the Clinical Trials Data Bank, 
http://www.clinicaltrials.gov. The sponsor-investigator has delegated responsibility to 
BTCRC AHQ for registering the trial and posting the results on clinicaltrials.gov.  
Information posted will allow subjects to identify potentially appropriate trials for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate trial locations and study site contact information. 


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14 
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Qin LX, Tang ZY, Ma ZC, et al: P53 immunohistochemical scoring: an 
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