Conditions: Non-small Cell Lung Cancer Stage IV
Keywords: NSCLC
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 31
Healthy volunteers: no

Brief summary:
This is a single arm, open label, Phase II study in KRAS-positive and KRAS-negative patients with stage IV (including pleural effusion) non squamous NSCLC who have failed two lines of anti-cancer therapy. A maximum of 60 evaluable patients with NSCLC will receive antroquinonol, of which 30 patients will be KRAS-positive and 30 patients KRAS-negative. An evaluable patient will have received at least one dose of antroquinonol and have a valid baseline tumor assessment. Enrollment will continue until the target number of evaluable patients has been enrolled.

Detailed description:
1. Progression free survival rate at 12 weeks, defined as the proportion of patients alive and progression free at Week 12. Patients will be progression free if they have no tumor assessments of progressive disease (defined according to RECIST guidelines, version 1.1) at any point from the start of treatment to Week 12.
2. Objective response rate (ORR), defined as the proportion of patients whose best overall response is either CR or PR according to RECIST version 1.1. The best overall response is the best response recorded during the first 12 week treatment cycle.
3. Disease control rate (DCR), defined as the proportion of patients with a documented CR, PR and SD during the first 12 week treatment cycle according to RECIST version 1.1.
4. Duration of overall tumor response (DR), defined as the interval between the date of the first observation of tumor response (CR or PR) and the date of disease progression or death.
5. Progression free survival defined as the time from randomization to objective tumor progression by RECIST version 1.1 or death due to any cause, whichever occurs first.
6. Overall survival (OS) defined as the time from randomization to death from any cause.
7. Time to progression (TTP) defined as the time from randomization to objective tumor progression by RECIST version 1.1.

Arms:
arm 1: patients will receive one 12 week cycle of antroquinonol 200 mg t.i.d. or until disease progression, unacceptable toxicity, non compliance or withdrawal of consent by the patient, or the investigator decides to discontinue treatment, whichever comes first.

Interventions: intervention 1: Antroquinonol
Intervention descriptions: intervention 1: patients will receive one 12 week cycle of antroquinonol 200 mg t.i.d. or until disease progression, unacceptable toxicity, non compliance or withdrawal of consent by the patient, or the investigator decides to discontinue treatment, whichever comes first.

Protocol document:
Prot_000.pdf: 
Golden Biotech 
CONFIDENTIAL 
06 December 2017 
Protocol (antroquinonol)  
 
 
 
Version 6, Final 
 
Page 1 of 90 
 
1 
TITLE PAGE 
CLINICAL STUDY PROTOCOL 
A Single-Arm, Open-Label, Phase II Trial Evaluating the Efficacy, Safety and 
Pharmacokinetics of Antroquinonol in Patients with Stage IV (including Pleural 
Effusion) Non-Squamous Non-Small Cell Lung Cancer (NSCLC) who have Failed Two 
Lines of Anti-Cancer Therapy 
 
Protocol No.: GHNSCLC-2-001 
EUDRACT/IND No.: 105226 
Test Product:  
Antroquinonol 100 mg capsules  
Indication: 
Non-small cell lung cancer (NSCLC) 
Sponsor: 
Golden Biotechnology Corporation 
Development Phase: 
II 
Sponsor Signatory: 
Dr. Howard Cheng 
Sponsor Medical Expert: 
Dr. Shou-Bao Wu 
Principal Investigator: 
David S. Ettinger, MD 
Date of the Protocol: 
06 December 2017 
Version of the Protocol: 
Version 6, Final 
 
The confidential information in this document is provided to you as an investigator, potential 
investigator or consultant for review by you, your staff and applicable Independent Ethics 
Committee and/or Institutional Review Board. It is understood that the information will not 
be disclosed to others without written authorization from Golden Biotechnology Corporation 
except to the extent necessary to obtain informed consent from those persons to whom the 
drug may be administered. 




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06 December 2017 
Protocol (antroquinonol)  
 
 
 
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Page 3 of 90 
 
INVESTIGATOR SIGNATURE PAGE 
 
PROTOCOL TITLE: A Single-Arm, Open-Label, Phase II Trial Evaluating the 
Efficacy, Safety and Pharmacokinetics of Antroquinonol in Patients with Stage IV 
(including Pleural Effusion) Non-Squamous Non-Small Cell Lung Cancer (NSCLC) 
who have Failed Two Lines of Anti-Cancer Therapy 
 
PROTOCOL NUMBER: GHNSCLC-2-001 
 
Golden Biotechnology Corporation 
 
I have read the attached protocol entitled “A single-arm, open-label, Phase II trial evaluating 
the efficacy, safety and pharmacokinetics of Antroquinonol in patients with stage IV 
(including pleural effusion) non-squamous non-small cell lung cancer (NSCLC) who have 
failed two lines of anti-cancer therapy”, dated 06 December 2017, and agree to abide by all 
provisions set forth therein. 
I agree to comply with the International Conference on Harmonization (ICH) Tripartite 
Guideline on Good Clinical Practice (GCP) and applicable Food and Drug Administration 
(FDA) regulations/guidelines set forth in 21 CFR Parts 11, 50, 54, 56 and 312. Also, the 
human-rights and privacy of the patients will be protected based on the Declaration of 
Helsinki. 
I agree to ensure that the confidential information contained in this document will not be used 
for any purpose other than the evaluation or conduct of the clinical investigation without the 
prior written consent of Golden Biotechnology Corporation. 
 
 
 
 
Signature of Investigator 
 
Date (day/month/year) 
 
 
 
 
 
 
Investigator Name (print or type) 
 
 
 
 
 
 
 
 
Investigator’s Title 
 
 
 
 
 
 
 
 
 


Golden Biotech 
CONFIDENTIAL 
06 December 2017 
Protocol (antroquinonol)  
 
 
 
Version 6, Final 
 
Page 4 of 90 
 
3 
GENERAL INFORMATION 
A Single-Arm, Open-Label, Phase II Trial Evaluating the Efficacy, Safety and 
Pharmacokinetics of Antroquinonol in Patients with Stage IV (including Pleural 
Effusion) Non-Squamous Non-Small Cell Lung Cancer (NSCLC) who have Failed Two 
Lines of Anti-Cancer Therapy 
 
Protocol No.: 
GHNSCLC-2-001 
Date of the Protocol: 
06 December 2017 
Sponsor: 
Golden Biotechnology Corporation 
 
15F, No. 27-6, Sec. 2, Jhong-Jheng E. Rd., 
 
Danshuei, Taipei 
 
County 251, Taiwan 
Clinical Research Organization: 
ICON Clinical Research Irl. Ltd (Headquarters) 
 
South County Business Park 
 
Leopardstown, 
 
Dublin 18 
 
Ireland 
Sponsor Signatory: 
Howard Cheng, Ph.D 
 
15F., No.27-6, Sec 2, Zhong-Zheng E. Rd. 
 
Tamsui Dist. New Taipei City 251 
 
Taiwan  
 
Tel No.: 886-2-28086006 
 
Fax No.: 886-2-28086007 
Sponsor Medical Expert: 
Shou-Bao Wu, MD  
 
15F., No.27-6, Sec 2, Zhong-Zheng E. Rd. 
 
Tamsui Dist. New Taipei City 251 
 
Taiwan  
 
Tel No.: 886-2-28086006 
 
Fax No.: 886-2-28086007 
Principal Investigator: 
David S. Ettinger, MD 
Johns Hopkins Sidney Kimmel Comprehensive Cancer 
Center 
 
401 N. Broadway 
 
Baltimore, MD 21231 
 
Tel No.: 410-955-8964 
 
ICON Clinical Laboratories: 
Samuel Reyes, Laboratory Project Manager II 
 
123 Smith Street 
 
Farmingdale, NY  11735 
 
Tel No.: 631-306-9652 
 
 
Fax No.: 631-603-5345 
 
 
ICON Central Laboratory Facility 
 
30 Loyang Way #02-15 
 
Loyang Industrial Estate  
 
Singapore (508), Singapore 508769   


Golden Biotech 
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06 December 2017 
Protocol (antroquinonol)  
 
 
 
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4 
STUDY SYNOPSIS 
 
Name of Sponsor/Company: 
Golden Biotechnology Corporation 
Individual Study 
Table Referring to Part of the 
Dossier: 
 
Volume: 
 
Page: 
(For National Authority Use Only) 
Name of Product: 
Hocena® 100 mg capsule 
Name of Active Ingredient: 
Antroquinonol 
Title of Study: 
A single-arm, open-label, Phase II study evaluating the efficacy, safety and pharmacokinetics of antroquinonol 
in patients with stage IV (including pleural effusion) non-squamous non-small cell lung cancer (NSCLC) who 
have failed two lines of anti-cancer therapy 
Principle Investigator: David S. Ettinger, MD; Johns Hopkins Sidney Kimmel Comprehensive Cancer      
Center, 401 N. Broadway, Baltimore, MD 21231, United States of America (USA). 
Study Centers: 
It is planned that at least 10 centers will be initiated for this study in the USA (nine centers) and Taiwan 
(one center).  
Publications: None. 
Planned Study Period: 
Third quarter, 2013 to fourth quarter, 2016  
Development Phase: 
Phase II 
Objectives: 
Primary Objective: 
To evaluate the activity of antroquinonol in unselected, KRAS-positive, and KRAS-negative patients with stage 
IV (including pleural effusion) non-squamous NSCLC who have failed two lines of anti-cancer therapy. 
Secondary Objective: 
To assess the safety and tolerability and pharmacokinetics (PK) of antroquinonol in patients with stage IV 
(including pleural effusion) non-squamous NSCLC who have failed two lines of anti-cancer therapy. 
Exploratory Objective: 
To explore potential relationships between of antroquinonol exposure and safety and efficacy endpoints. 
Methodology: 
This is a single-arm, open-label, Phase II study in KRAS-positive and KRAS-negative patients with stage IV 
(including pleural effusion) non-squamous NSCLC who have failed two lines of anti-cancer therapy. This is 
defined as patients with radiologically confirmed disease progression following greater than or equal to two, but 
less than or equal to four, prior lines of systemic anti-cancer therapy (see Inclusion Criteria). A maximum of 
60 evaluable patients with NSCLC will receive antroquinonol, of which 30 patients will be KRAS-positive and 
30 patients KRAS-negative. An evaluable patient will have received at least one dose of antroquinonol and have 
a valid baseline tumor assessment (see Statistical Methods). Enrollment will continue until the target number of 
evaluable patients has been enrolled. 
Written informed consent must be obtained from all patients before initiating Screening. The Screening period 
will be up to 42 days in duration (Days -42 to -1). Following completion of all Screening assessments and 
confirmation of eligibility criteria, patients will receive antroquinonol 200 mg three times a day (t.i.d. at 8-hour 
intervals) on Day 0 for 12 weeks (one treatment cycle) or until documented evidence of disease progression, 
unacceptable toxicity, non-compliance or withdrawal of consent by the patient, or the investigator decides to 
discontinue treatment, whichever comes first. Study drug should be taken at 8-hour intervals. The time of study 
drug administration should be recorded in the patient diary. 
After the first 12-week treatment cycle, patients who are progression-free will be eligible to receive further 
(12-week) treatment cycles with antroquinonol (Extension Phase), until documented evidence of disease 
progression, unacceptable toxicity, non-compliance or withdrawal of consent by the patient, or the investigator 
decides to discontinue treatment, whichever comes first. 
Patients will attend study visits on Days 0, 14, 28, 42, 56 and 84 during the first 12-week treatment cycle, every 
4 weeks during the second, third, and fourth treatment cycles (Extension Phase), and every 12 weeks during 


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CONFIDENTIAL 
06 December 2017 
Protocol (antroquinonol)  
 
 
 
Version 6, Final 
 
Page 6 of 90 
 
Name of Sponsor/Company: 
Golden Biotechnology Corporation 
Individual Study 
Table Referring to Part of the 
Dossier: 
 
Volume: 
 
Page: 
(For National Authority Use Only) 
Name of Product: 
Hocena® 100 mg capsule 
Name of Active Ingredient: 
Antroquinonol 
subsequent treatment cycles (Extension Phase).  
The study-specific procedures include: physical examination, vital signs, 12-lead electrocardiogram (ECG), 
performance status, clinical laboratory tests, adverse events (AEs), concomitant medication and patient 
compliance.  
Patients discontinuing the study will attend an End of Study Visit, 4 weeks after the last administration of study 
drug. 
Intensive PK sampling will be performed on Days 0 and 28 in all patients enrolled in Stage 1. Sparse PK 
sampling will be performed on Days 28, 42, and 56 in all patients enrolled in Stage 2. 
All patients who discontinue from study drug, but consent to be followed up for survival status, will be followed 
up by telephone contact every 3 months, for a maximum of 6 months from the date of last administration of 
study drug or death, whichever occurs first. 
Tumor assessments will be performed at Screening, Day 42 and Day 84 using the Response Evaluation Criteria 
in Solid Tumors (RECIST) criteria version 1.1. Tumor assessments will be performed every 12 weeks during 
the Extension Phase. 
The primary efficacy endpoint is progression-free survival (PFS) rate at 12 weeks, which is defined as the 
proportion of patients alive and progression-free at Week 12. Patients will be progression-free if they have no 
evidence of progressive disease (defined according to RECIST guidelines, version 1.1) from the start of 
treatment to Week 12. 
The study uses a two-stage design seeking to detect a true PFS rate of more than 35% in the overall (unselected) 
population and 40% within the KRAS tumor mutation positive and negative strata. Thirty evaluable 
patients (15 in each stratum) will be treated initially (Stage 1), with expansion to a maximum of 60 evaluable 
patients (Stage 2). The rules for continuing the overall study and individual stratum are given in the Statistical 
Methods below. 
An Independent Data Monitoring Committee will act in an advisory capacity to monitor patient safety and 
efficacy data from the study. The members will be selected on the basis of relevant experience and 
understanding of clinical research and the issues specific to the therapeutic area, as well as previous data 
monitoring committee experience. 
Number of Patients: 
The study uses a two-stage design. Thirty evaluable patients (15 in each stratum) will be treated initially 
(Stage 1), with expansion to a maximum of 60 evaluable patients (Stage 2). Enrollment will continue until the 
target number of evaluable patients has been enrolled. 
Diagnosis and Main Criteria for Inclusion: 
Inclusion criteria 
Patients eligible for enrollment in the study must meet all of the following criteria: 
• 
Cytologically or histologically confirmed non-squamous NSCLC Stage IV (including pleural effusion). 
• 
Radiologically confirmed disease progression following greater than or equal to two, but less than or equal 
to four, prior lines of systemic anti-cancer therapy, one of which should be a platinum-based regimen, OR 
the patient has refused treatment with approved treatment modalities, OR the investigator feels that the 
patient is not a candidate for other systemic therapy. Patients with epidermal growth factor receptor 
(EGFR)-positive mutations should have been offered treatment with an EGFR-TK inhibitor prior to 
enrolment in this study. Adjuvant therapy with or without maintenance therapy would count as one line of 
systemic therapy. A line of therapy requires at least two 3-4 week complete cycles unless it was stopped due 
to toxicity, in which case it would count as one line of therapy 
• 
At least one radiologically measurable target lesion per RECIST version 1.1 
• 
Fresh or archival biopsy tissue available to determine KRAS tumor mutation status 
• 
At least 18 years of age at the time of signing informed consent 
• 
Life expectancy of at least 3 months 


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06 December 2017 
Protocol (antroquinonol)  
 
 
 
Version 6, Final 
 
Page 7 of 90 
 
Name of Sponsor/Company: 
Golden Biotechnology Corporation 
Individual Study 
Table Referring to Part of the 
Dossier: 
 
Volume: 
 
Page: 
(For National Authority Use Only) 
Name of Product: 
Hocena® 100 mg capsule 
Name of Active Ingredient: 
Antroquinonol 
• 
Written informed consent that is consistent with International Conference on Harmonisation Tripartite 
Guideline on Good Clinical Practice guidelines 
• 
Patient or legally acceptable representative has granted written informed consent before any study-specific 
procedures (including special Screening tests) are performed 
• 
Eastern Cooperative Oncology Group (ECOG) performance score of 0, 1 or 2 
• 
Hemoglobin ≥ 9.0 g/dL; platelets ≥ 100 x 109/L; absolute neutrophil count ≥ 1.5 x 109/L without the use of 
hematopoietic growth factors 
• 
Bilirubin and creatinine less than 2 × upper limit of normal (ULN) for the institution 
• 
Albumin ≥ 2.5 g/dL 
• 
Aspartate aminotransferase and alanine aminotransferase less than 5 × ULN for the institution 
• 
Prothrombin time less than 1.5 × ULN for the institution 
• 
Potassium, magnesium and phosphorus within the normal range for the institution (supplementation is 
permissible) 
• 
Willing to use two medically accepted and effective methods of contraception from the list below during 
the study (both men and women as appropriate) and for 3 months after the last dose of study drug: 
− 
Established use of oral, injected or implanted hormonal methods of contraception. 
− 
Placement of an intrauterine device or intrauterine system. 
− 
Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with 
spermicidal foam/gel/film/cream/suppository. 
− 
Male sterilization (with the appropriate post-vasectomy documentation of the absence of sperm in the 
ejaculate). 
− 
True abstinence: When this is in line with the preferred and usual lifestyle of the patient. 
• 
Recovery to ≤ Grade 1 or baseline of any toxicities due to prior treatments, excluding alopecia  
Exclusion criteria 
Patients meeting any of the following criteria must not be enrolled in the study: 
• 
Chemo-, hormone- or immunotherapy, within 4 weeks or within less than four half-lives of the date of first 
administration of study drug and/or persistence of toxicities of prior anti-cancer therapies which are deemed 
to be clinically relevant 
• 
Radiotherapy within the past 2 weeks prior to the date of first administration of study drug 
• 
Previous treatment with an histone deacetylase inhibitor or an EGFR inhibitor within at least 4 weeks of the 
date of first administration of study drug 
• 
Treatment with any drug(s) known to be a strong inhibitor or inducer of cytochrome P450 (CYP)2C19, 
CYP3A4, CYP2C8, and CYP2E1, within 14 days of the date of first administration of study drug 
• 
Brain metastases which are symptomatic; patients with treated brain metastases are eligible with stable 
brain disease for at least 4 weeks without the requirement for steroids or anti-epileptic therapy 
• 
Inability to swallow oral medications or a recent acute gastrointestinal disorder with diarrhea e.g., Crohn’s 
disease, malabsorption, or Common Terminology Criteria for Adverse Event (CTCAE) Grade > 2 diarrhea 
of any etiology at baseline 
• 
Other malignancies diagnosed within the past five years (other than curatively treated cervical cancer in 
situ, non-melanoma skin cancer, superficial bladder tumors Ta [non-invasive tumor] and TIS [carcinoma in 
situ], or non-metastatic prostate cancer stage 1 to 2, which has been previously treated with surgery or 
radiation therapy, and serum prostate-specific antigen is within normal limits [test performed within the past 
12 months prior to the date of first administration of study drug]) 
• 
Patients with any serious active infection (i.e., requiring an intravenous antibiotic, antifungal, or antiviral 
agent) 
• 
Patients with known human immunodeficiency virus, active hepatitis B or active hepatitis C 


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06 December 2017 
Protocol (antroquinonol)  
 
 
 
Version 6, Final 
 
Page 8 of 90 
 
Name of Sponsor/Company: 
Golden Biotechnology Corporation 
Individual Study 
Table Referring to Part of the 
Dossier: 
 
Volume: 
 
Page: 
(For National Authority Use Only) 
Name of Product: 
Hocena® 100 mg capsule 
Name of Active Ingredient: 
Antroquinonol 
• 
Patients who have any other life-threatening illness or organ system dysfunction, which in the opinion of 
the investigator, would either compromise patient safety or interfere with the evaluation of the safety of the 
study drug 
• 
Known or suspected substance abuse or alcohol abuse 
• 
Women of child-bearing potential or men who are able to father a child unwilling to use two medically 
accepted and effective methods of contraception during the study (as specified in the inclusion criteria) 
• 
Pregnancy or breast feeding 
• 
Patient unable to comply with the protocol 
• 
History of clinically significant or uncontrolled cardiac disease, including congestive heart failure, angina, 
myocardial infarction, arrhythmia, including New York Heart Association functional classification of three 
Test Product, Dose and Mode of Administration: 
Antroquinonol 100 mg. Beginning on Day 0, patients will receive one 12-week cycle of antroquinonol 200 mg 
t.i.d. or until disease progression, unacceptable toxicity, non-compliance or withdrawal of consent by the 
patient, or the investigator decides to discontinue treatment, whichever comes first. 
Study drug should be taken at 8-hour intervals with a glass of water, approximately 15 minutes after a meal or 
light snack, and not within ±1 hour of drinking an ethanol-containing beverage, e.g. an alcoholic drink. The date 
and time of each study drug administration should be recorded in the patient diary. 
After the first 12-week treatment cycle, patients who are progression-free will be eligible to receive further 
(12-week) treatment cycles with antroquinonol (Extension Phase), until documented evidence of disease 
progression, unacceptable toxicity, non-compliance or withdrawal of consent by the patient, or the investigator 
decides to discontinue treatment, whichever comes first. Investigators should wait at least 7 days after the last 
administration of study drug before initiating alternative treatment.  
Reference Therapy, Dose and Duration of Administration: 
Not applicable. 
Duration of Treatment: 
Patients can be treated with antroquinonol, until documented evidence of disease progression, unacceptable 
toxicity, non-compliance or withdrawal of consent by the patient, or the investigator decides to discontinue 
treatment, whichever comes first. 
Variables: 
The primary and secondary efficacy analyses will be based on independent centralized assessment of medical 
images. 
Efficacy: 
Primary endpoint 
The primary endpoint is as follows: 
• 
Progression-free survival rate at 12 weeks, defined as the proportion of patients alive and progression-free 
at Week 12. Patients will be progression-free if they have no evidence of progressive disease (defined 
according to RECIST guidelines, version 1.1) from the start of treatment to Week 12. 
 
Tumor response will be assessed at 6-week intervals during the first treatment cycle using the RECIST 
 
criteria, version 1.1. Each patient will be assigned one of the following categories: 1) complete 
 
response (CR), 2) partial response (PR), 3) stable disease (SD), or 4) progressive disease (PD). Patients 
 
who died from any cause or discontinued the study for any reason without a post-screening or Week 12 
 
tumor assessment will be considered as failing to respond to treatment. 
Secondary efficacy endpoints 
Secondary efficacy endpoints are as follows: 
• 
Objective response rate (ORR), defined as the proportion of patients whose best overall response is either 
CR or PR according to RECIST version 1.1. The best overall response is the best response recorded during 


Golden Biotech 
CONFIDENTIAL 
06 December 2017 
Protocol (antroquinonol)  
 
 
 
Version 6, Final 
 
Page 9 of 90 
 
Name of Sponsor/Company: 
Golden Biotechnology Corporation 
Individual Study 
Table Referring to Part of the 
Dossier: 
 
Volume: 
 
Page: 
(For National Authority Use Only) 
Name of Product: 
Hocena® 100 mg capsule 
Name of Active Ingredient: 
Antroquinonol 
the first 12-week treatment cycle. 
• 
Disease control rate (DCR), defined as the proportion of patients with a documented CR, PR and SD during 
the first 12-week treatment cycle according to RECIST version 1.1. 
• 
Duration of overall tumor response (DR), defined as the interval between the date of the first observation of 
tumor response (CR or PR) and the date of disease progression or death. 
• 
Progression-free survival defined as the time from the date of first administration of study drug to objective 
tumor progression by RECIST version 1.1 or death due to any cause, whichever occurs first. 
• 
Overall survival (OS) defined as the time from the date of first administration of study drug to death from 
any cause. 
• 
Time to progression (TTP) defined as the time from the date of first administration of study drug to 
objective tumor progression by RECIST version 1.1. 
Patient Reported Outcome endpoint 
The Patient Reported Outcome (PRO) endpoint is as follows: 
• 
European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire 
(QLQ) C30 (QLQ-C30) and EORTC QLQ – Lung Cancer Module (QLQ-LC13)  
Pharmacokinetics: 
PK endpoints will be derived for intensively sampled PK profiles by non-compartmental methods and include: 
• 
Cmax: peak concentration 
• 
Ctrough: trough plasma concentration 
• 
Tmax: peak time 
• 
AUCτ: area under the plasma concentration-time curve over the 8-hour dosing interval 
• 
T½: terminal half-life 
• 
Vz/F: apparent volume of distribution during elimination 
• 
CL/F: apparent oral clearance 
• 
T½, eff: effective half-life 
If possible, PK data from all patients will be analyzed using population-based PK (PopPK) methods and post 
hoc estimates of antroquinonol exposure (i.e., Cmax, Ctrough and AUCτ) computed for exploration of potential 
exposure-response relationships. 
Safety: 
The safety endpoints are the incidence of reported AEs and abnormal laboratory tests. Adverse events will be 
assessed using the National Cancer Institute (NCI) CTCAE version 4.03. 
Tumor biomarkers: 
Subgroup analyses will assess the predictive value of tumor biomarkers. 
Statistical Methods: 
Sample size and power: 
The statistical design is based on literature published by Green and Dahlberg (1992), von Mehren et. al. (2012), 
and Hoang et. al. (2013). It is assumed that within each of the KRAS tumor mutation positive and negative 
strata, a PFS rate at 12 weeks of 40% and 35% overall (unselected) population will be of interest. Further testing 
will not be pursued if the PFS rate at 12 weeks is less than 15%. 
Initially, 15 evaluable patients are to be accrued within each stratum. If two or more patients are alive and 
progression-free at Week 12 within a stratum, then an additional 15 evaluable patients will be accrued to that 
stratum for a total of 30 evaluable patients. 
If nine or more patients are alive and progression-free at Week 12 within the 30 evaluable patients in the stratum 
then antroquinonol will be considered worthy of further study in that cohort. This design will allow a 
significance level of 2.8% and a power of 90.5% within each stratum. 


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Name of Sponsor/Company: 
Golden Biotechnology Corporation 
Individual Study 
Table Referring to Part of the 
Dossier: 
 
Volume: 
 
Page: 
(For National Authority Use Only) 
Name of Product: 
Hocena® 100 mg capsule 
Name of Active Ingredient: 
Antroquinonol 
In addition to within-stratum hypothesis testing, this study is also designed to investigate the PFS rate at 
12 weeks in the overall (unselected) population. If less than three patients are alive and progression-free at 
Week 12 in the first 20 evaluable patients and, the criterion for continuing the individual stratum are not met, 
then the accrual for all strata will be discontinued. Otherwise, a maximum of 40 additional evaluable patients 
will be entered (depending on whether any individual stratum is closed). Fifteen or more patients alive and 
progression-free at Week 12 out of the maximum 60 evaluable patients would warrant further study. 
The overall design has a significance level of 2.8% (probability of falsely declaring the regimen with a 15% PFS 
rate at 12 weeks to warrant further study) and power 95.6% (probability of declaring the regimen with a 35% 
PFS rate at 12 weeks in the overall population to warrant further study). 
Efficacy: 
Except for the primary efficacy analysis, there will be no formal statistical testing. All data will be summarized 
and listed as appropriately. All efficacy endpoints will be evaluated in both the overall (unselected) population 
and within-stratum. 
The primary analysis will be performed on the evaluable population. The evaluable population will consist of all 
enrolled patients who receive at least one dose of antroquinonol and have a valid baseline tumor assessment. A 
valid baseline assessment is defined as a readable scan performed within 14 (± 7) days of the date of first 
administration of study drug. For the efficacy analysis, enrollment will continue until the target number of 
evaluable patients has been enrolled. 
The full analysis set (FAS) and per-protocol set (PPS) will be used for supportive efficacy analyses. The FAS 
will consist of patients in the evaluable population who have at least one post-baseline tumor assessment. The 
PPS will consist of patients in the FAS who do not have any major protocol violations. 
The primary analysis will follow the two stage procedure, as specified in the sample size section. All secondary 
efficacy endpoints will be reported with category counts, percentage and 95% confidence interval (CI). All 
time-to-event endpoints, PFS, OS and TTP will be evaluated using Kaplan-Meier estimates and curves will be 
generated based on these estimates. 
Safety: 
All patients who are treated with at least one dose of study drug will be evaluated for safety. Safety data will be 
summarized for the overall (unselected) population and within-stratum. There will be no formal statistical 
analysis of safety data. Demographic and Screening data will be listed and summarized, as appropriate. All AEs 
will be coded using the Medical Dictionary for Regulatory Activities, graded using the NCI CTCAE 
version 4.03 and listed by patient. Treatment-emergent AEs will be summarized by treatment, severity and 
causal relationship to study drug. Any serious AEs will be listed separately. System organ class and preferred 
terms within each body system will be used for frequency summaries. Clinical laboratory data, vital signs and 
ECG data will be listed by patient and summarized, as appropriate. 
Patient Reported Outcome: 
The PRO population will consist of all patients who have completed the QLQ on Day 0 and on at least one 
occasion after the first administration of study drug. All data will be summarized and listed, as appropriate. 
Patient Reported Outcome data will be summarized for the overall (unselected) population and within-stratum. 
Pharmacokinetics: 
Non-compartmental PK analysis will be performed for the PK population. The PK population will consist of 
patients in the first stage who have an evaluable PK profile, defined as a profile from which at least one of the 
PK parameters stated as endpoints can be estimated, and no protocol deviations that would affect the PK of 
antroquinonol. Descriptive statistics will be presented for all PK parameters. The PopPK methods will be used 
to estimate exposure metrics for patients with at least two plasma concentrations and sufficient and reliable 
dosing histories. 
Tumor biomarkers: 
The predictive value of tumor biomarkers will be assessed in appropriate subgroup analyses. Full details of this 
analysis will be provided in the Statistical Analysis Plan.  
Date of the Protocol: 06 December 2017 


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5 
TABLE OF CONTENTS 
1 
TITLE PAGE ................................................................................................................. 1 
2 
SIGNATURE PAGES ................................................................................................... 2 
3 
GENERAL INFORMATION ........................................................................................ 4 
4 
STUDY SYNOPSIS ...................................................................................................... 5 
5 
TABLE OF CONTENTS ............................................................................................ 11 
5.1 
List of Tables .................................................................................................. 14 
5.2 
List of Figures................................................................................................. 14 
5.3 
List of Appendices and Supplements ............................................................. 14 
6 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ................................ 15 
7 
INTRODUCTION ....................................................................................................... 18 
7.1 
Background..................................................................................................... 18 
7.2 
Investigational Product ................................................................................... 18 
7.3 
Preclinical Data .............................................................................................. 19 
7.4 
Clinical Study Data – Phase 1 Study .............................................................. 20 
7.5 
Rationale for the Study ................................................................................... 22 
8 
STUDY OBJECTIVES ............................................................................................... 23 
8.1 
Primary Objective ........................................................................................... 23 
8.2 
Secondary Objective ....................................................................................... 23 
8.3 
Exploratory Objective .................................................................................... 23 
9 
INVESTIGATIONAL PLAN ...................................................................................... 24 
9.1 
Overall Study Design and Plan....................................................................... 24 
9.1.1 
Description ................................................................................................. 24 
9.1.2 
Schedule of Assessments ........................................................................... 25 
9.1.3 
Study Procedures ....................................................................................... 30 
9.1.3.1 
Screening (up to 42 days before Day 0) ..................................... 30 
9.1.3.2 
Visit 1 (Day 0) ............................................................................ 30 
9.1.3.3 
Visit 2 (Day 14 ± 3) .................................................................... 31 
9.1.3.4 
Visit 3 (Day 28 ± 3) .................................................................... 31 
9.1.3.5 
Visit 4 (Day 42 ± 3) .................................................................... 32 
9.1.3.6 
Visit 5 (Day 56 ± 3) .................................................................... 32 
9.1.3.7 
Visit 6 (Day 84 ± 3) .................................................................... 33 
9.1.3.8 
End of Study (EOS) Visit (± 7 days) .......................................... 33 
9.1.3.9 
Extension Phase Visits (± 7 days) .............................................. 34 
9.2 
Discussion of Study Design............................................................................ 34 
9.2.1 
Rationale for Single-Arm, Open-Label Phase II Study ............................. 34 
9.2.2 
Appropriateness of Measurements ............................................................. 36 
9.2.3 
Risk/Benefit and Ethical Assessment ........................................................ 37 


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9.2.4 
Early Termination ...................................................................................... 37 
9.3 
Selection of Study Population ........................................................................ 37 
9.3.1 
Inclusion Criteria ....................................................................................... 37 
9.3.2 
Exclusion Criteria ...................................................................................... 38 
9.3.3 
Removal of Patients from Study or from Study Treatment ....................... 39 
9.3.4 
Follow-Up for Drug Discontinuation/Patient Withdrawal from Study ..... 40 
10 
TREATMENT OF PATIENTS ................................................................................... 41 
10.1 
Study Drug Treatment and Dosing ................................................................. 41 
10.2 
Treatment for Study Drug Overdose .............................................................. 41 
10.3 
Administration on Pharmacokinetic Sampling Days ..................................... 41 
10.4 
Extension Phase .............................................................................................. 41 
10.5 
Dose Modification .......................................................................................... 42 
10.6 
Packaging and Labeling ................................................................................. 42 
10.7 
Dispensing and Return of Study Drug............................................................ 43 
10.8 
Storage and Reconciliation of Supplies .......................................................... 43 
10.9 
Concomitant Medications ............................................................................... 43 
10.10 
Prohibited Medications, Foods and Tobacco Use .......................................... 43 
10.11 
Treatment Compliance ................................................................................... 44 
11 
ASSESSMENT OF EFFICACY ................................................................................. 45 
11.1 
Efficacy Variables .......................................................................................... 45 
11.2 
Efficacy Assessments ..................................................................................... 46 
11.2.1 
Tumor Measurement .................................................................................. 46 
11.2.2 
Clinical Response – Solid Tumors ............................................................. 47 
11.2.3 
Tumor Biomarkers ..................................................................................... 47 
12 
PHARMACOKINETICS ............................................................................................ 48 
12.1 
Pharmacokinetic Sampling ............................................................................. 48 
12.2 
Pharmacokinetic Sampling Procedures .......................................................... 48 
12.2.1 
Blood Samples ........................................................................................... 48 
12.2.2 
Sample Storage and Shipping .................................................................... 48 
12.2.3 
Analytical Methodology ............................................................................ 49 
13 
ASSESSMENT OF SAFETY...................................................................................... 50 
13.1 
Height and Weight .......................................................................................... 50 
13.2 
Demographics ................................................................................................. 50 
13.3 
Medical History .............................................................................................. 50 
13.4 
Previous and Concomitant Medications ......................................................... 50 
13.5 
Physical Examination ..................................................................................... 50 
13.6 
Vital Signs ...................................................................................................... 50 
13.7 
Electrocardiograms ......................................................................................... 50 
13.8 
Eastern Cooperative Oncology Group Performance Status ........................... 50 
13.9 
Laboratory Variables ...................................................................................... 51 
13.10 
Adverse Events ............................................................................................... 51 


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13.10.1 Disease-Related Events.............................................................................. 52 
13.10.2 Lack of Efficacy ........................................................................................ 52 
13.10.3 Clinical Laboratory Abnormalities ............................................................ 52 
13.10.4 Recording AEs and SAEs .......................................................................... 52 
13.10.5 Serious Adverse Events ............................................................................. 53 
13.10.6 Pregnancy .................................................................................................. 54 
14 
STATISTICAL EVALUATION ................................................................................. 56 
14.1 
Sample Size and Power .................................................................................. 56 
14.2 
Statistical Methods ......................................................................................... 56 
14.2.1 
Analysis Populations ................................................................................. 56 
14.2.2 
Efficacy Analysis ....................................................................................... 57 
14.2.2.1 Primary Efficacy Analysis .......................................................... 57 
14.2.2.2 Secondary Efficacy Analysis ...................................................... 57 
14.2.3 
Pharmacokinetic Analysis.......................................................................... 58 
14.2.4 
Safety Analysis .......................................................................................... 59 
14.2.5 
Patient Reported Outcome ......................................................................... 59 
14.3 
Interim Analysis ............................................................................................. 59 
14.4 
Tumor Biomarkers.......................................................................................... 60 
14.5 
Data Monitoring Committee........................................................................... 60 
15 
DATA HANDLING AND RECORD KEEPING ....................................................... 61 
15.1 
Informed Consent and Institutional Review ................................................... 61 
15.2 
Confidentiality/Publication of the Study ........................................................ 61 
15.3 
Data Collection ............................................................................................... 61 
15.4 
Drug Accountability ....................................................................................... 61 
15.5 
Record Retention ............................................................................................ 62 
15.6 
Case Report Forms ......................................................................................... 62 
15.7 
Source Documents .......................................................................................... 62 
16 
MONITORING............................................................................................................ 63 
17 
QUALITY CONTROL AND QUALITY ASSURANCE .......................................... 64 
18 
PROTOCOL AMENDMENT AND PROTOCOL DEVIATION .............................. 65 
18.1 
Protocol Amendment ...................................................................................... 65 
18.2 
Protocol Deviations ........................................................................................ 65 
19 
ETHICAL CONSIDERATIONS ................................................................................ 66 
20 
FINANCING AND INSURANCE .............................................................................. 67 
21 
PUBLICATION POLICY ........................................................................................... 68 
22 
REFERENCE LIST ..................................................................................................... 69 
23 
APPENDICES ............................................................................................................. 72 
Appendix 1 
Revised Response Evaluation Criteria in Solid Tumors 
Guidelines Version 1.1 – Adaptation from original publication with 
addition of supplementary explanations ......................................................... 72 


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Appendix 2 
Eastern Co-Operative Oncology Group Evaluation ......................... 81 
Appendix 3 
European Organisation for Research and Treatment of Cancer 
Quality of Life Questionnaire C30 and Lung Cancer Module (LC13) .......... 82 
Appendix 4 
Reference List of Known Inducers, Inhibitors and Substrates of 
Selected Cytochrome P450 Enzymes ............................................................. 85 
Appendix 5 
Declaration of Helsinki .................................................................... 87 
 
5.1 
List of Tables 
Table 9.1 
Schedule of Study-Specific Procedures ............................................................. 26 
Table 9.2 
Schedule of Blood Sampling .............................................................................. 29 
Table 10.1 
Dose Modification and Management of Drug Toxicity Guidelines ................... 42 
 
5.2 
List of Figures 
Not applicable. 
 
5.3 
List of Appendices and Supplements 
Appendix 1 
Revised Response Evaluation Criteria in Solid Tumors Guidelines 
Version 1.1  
Appendix 2 
Eastern Co-Operative Oncology Group Evaluation 
Appendix 3 
European Organisation for Research and Treatment of Cancer Quality of Life 
Questionnaire C30 and Lung Cancer Module (LC13)  
Appendix 4 
Reference List of Known Inducers, Inhibitors and Substrates of Selected 
Cytochrome P450 Enzymes 
Appendix 5 
Declaration of Helsinki 
 
 


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6 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition 
AE 
Adverse event 
Akt 
Protein kinase B 
ALT 
Alanine aminotransferase 
AMES 
Bacteria reversed mutation assay 
AST 
Aspartate aminotransferase 
AUC0-24 
Area under the plasma concentration-time curve from 0 to 24 hours 
AUCτ  
Area under the plasma concentration-time curve over the 8-hour 
dosing interval 
BMI 
Body mass index 
CFR 
Code of Federal Regulations  
CHMP 
Committee for Medicinal Products for Human Use 
CI 
Confidence interval 
CL/F 
Apparent oral clearance 
Cmax 
Peak concentration 
CR 
Complete response 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
Ctrough 
Trough plasma concentration 
CYP 
Cytochrome P450 
DCR 
Disease control rate 
DLT 
Dose limiting toxicity 
DR 
Duration of overall tumor response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EDC 
Electronic data capture 
EGFR 
Epidermal growth factor receptor 
EMA 
European Medicines Agency 
EORTC 
European Organization for Research and Treatment of Cancer 
EOS 
End of Study 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
FFPE 
Formalin fixed paraffin embedded 
FTase 
Farnesyltransferase 
GCP 
Good Clinical Practice 
HCl 
Hydrogen chloride 


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Abbreviation 
Definition 
HDAC 
Histone deacetylase 
HIV 
Human immunodeficiency virus 
HR 
Heart rate 
HNSTD 
Highest non-severely toxic dose 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
MAPK 
mitogen-activated protein kinase  
MedDRA 
Medical Dictionary for Regulatory Activities 
MTD 
Maximum tolerated dose 
MRI 
Magnetic resonance imaging 
MSAP 
Modeling and simulation analysis plan 
NCCN 
National Comprehensive Cancer Network 
NCI  
National Cancer Institute 
NOAEL 
No observed adverse effect level 
NSAID 
Non-steroidal anti-inflammatory drugs 
NSCLC 
Non-small cell lung cancer 
ORR 
Objective response rate 
OS 
Overall survival 
PD 
Progressive disease 
PFS 
Progression-free survival 
PI 
Principal investigator 
PK 
Pharmacokinetic 
PopPK 
Population-based pharmacokinetic 
PPS 
Per-protocol set 
PR 
Partial response 
PRO 
Patient Reported Outcome 
QLQ 
Quality of Life Questionnaires 
QoL 
Quality of Life 
QTc 
Corrected QT 
REB 
Research Ethics Board 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SCLC 
Small cell lung cancer 
SD 
Stable disease 
TEAE 
Treatment-emergent adverse event 


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Abbreviation 
Definition 
T½ 
Terminal half-life 
T½, eff 
Effective half-life 
Tmax 
Peak time  
t.i.d. 
Three-times-a-day 
TTP 
Time to progression 
ULN 
Upper limit of normal 
US 
United States 
Vz/F 
Apparent volume of distribution during elimination 


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7 
INTRODUCTION 
7.1 
Background 
Lung cancer is the most frequently diagnosed major cancer in the world and leading cause of 
cancer mortality worldwide. In the United States of America (USA), it is estimated that 
219,440 new cases of lung cancer (116,090 men and 103,350 women) will be diagnosed and 
159,390 deaths will be related to this malignancy in 2009.1 In Taiwan, 8,748 new cases of 
lung cancer were diagnosed in 2006, accounting for 11.94% of cancer diagnoses, and 
7,479 patients died of this disease, contributing to 19.68% cancer deaths. The mortality was 
44.42 and 20.65 per 100,000 men and women, respectively.2  
Lung cancers are categorized on the basis of important prognostic and therapeutic 
implications as either non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC). 
Non-small cell lung cancer contributed to about 80% of new cases diagnosed each year.3 
NSCLC typically proliferates slower with lower doubling time than SCLC and can be 
characterized as three primary histologic types: adenocarcinoma, squamous cell, and large 
cell carcinoma. Adenocarcinoma has become the dominant histologic type of NSCLC and is 
the most common type in women and non-smokers.3 It typically arises in the periphery with 
glandular differentiation or mucin production, forms tubular or papillary structures, and 
metastasizes widely and early, compared to squamous carcinoma.3 
About 70% of NSCLC patients are diagnosed with advanced, poor-prognosis stage III or IV 
disease (approximately 50% for stage IV).4 The majority of these advanced tumors are 
considered inoperable due to disseminated (multiple sites) metastatic disease or metastatic 
sites that are not amendable to local therapy. For these patients, platinum-based 
chemotherapy is the standard treatment recommended by American Society of Clinical 
Oncology and National Comprehensive Cancer Network (NCCN).5,6 Available treatment 
options, including systemic therapy using non-specific cytotoxic chemotherapy or targeted 
therapies, for advanced NSCLC have progressed significantly in the past two decades; 
however, survival for indicated patients remains modest.7 In addition, treatment for stage IV 
lung cancer remains a disappointment. Future directions toward new therapy are therefore 
necessary. 
7.2 
Investigational Product 
Antroquinonol, trade name Hocena®, a novel cyclohexenone compound, is a purified 
compound from extract of Antrodia camphorata. Antrodia camphorata is an endemic species 
in Taiwan, and has been traditionally used for food and drug intoxication, and the treatment 
of diarrhea, abdominal pain, hypertension, itching of the skin, and liver cancer.8 Other 
research has shown Antrodia camphorata to have detoxification,9,10 anti-inflammatory, 11,12 
immunomodulatory,13 liver protection,14 and anti-cancer effects.15-21 The mycelium of 
Antrodia camphorata has been marketed as a food supplement by Golden Biotechnology 
Corporation since 2005 and this product was further tested and found to be safe and 
efficacious in nonclinical settings. It was approved as a functional food for improving liver 
health by the Department of Health in Taiwan in 2008. 


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The marketed food supplement product contains 1.1 mg antroquinonol per capsule and the 
recommended dosage is three capsules per intake twice daily (six capsules per day). The 
cumulative exposure in humans is over 7.8 million capsules, translating to 8.6 kg of 
antroquinonol for duration of approximately 4 years. 
7.3 
Preclinical Data 
Antroquinonol caused cell death with an IC50 of 2.22 to 6.42 µM for different cancer cell 
lines. Antroquinonol significantly enhanced the ratio of unprocessed to processed Ras in lung 
cancer cells in a dose-dependent manner (P < 0.01) and this enhancement was competed by 
farnesyl pyrophosphate. Antroquinonol inhibited farnesyltransferase (FTase) activity and 
molecular docking analysis predicted that the isoprene unit and the 4’-hydroxy group of 
antroquinonol may play important roles in the interaction between antroquinonol and FTase. 
In addition, antroquinonol increased the expression level of beclin-1 (three-fold), LC3-II/I 
(P < 0.01) and PC3 puncta formation in lung cancer cells. Antroquinonol may therefore 
inhibit Ras activation through inhibition of FTase, leading to autophagic cell death. 
Previous studies revealed that antroquinonol triggers anti-tumor activity through several 
signaling molecules, including AMPK, PI3K, and mTOR. Recent research suggests that 
antroquinonol indirectly inhibits Ras processing through inhibition of FTase activity. The 
Ras-PI3K-Akt-mTOR pathway, which is associated with proliferation, motility, metabolism, 
and differentiation, is inhibited in response to antroquinonol. Thus, antroquinonol may 
promote its anti-cancer effects by regulating cross talk in a complex signaling network that 
results in apoptosis and autophagy. 
An in vivo study in non-obese diabetes/severe combined immunodeficiency mice with A549 
subcutaneous xenografts consistently showed tumor growth suppression results after 2 weeks 
of oral 30 and 60 mg/kg antroquinonol treatment. Safety pharmacology studies including 
central nervous system effect in Sprague-Dawley rat, binding activity with hERG ion channel 
in in vitro setting, cardiovascular effect in beagle dogs and respiratory system effect study in 
Sprague-Dawley rat were all completed and the results showed no particular safety concerns 
of antroquinonol. Pharmacokinetic (PK) studies including absolute bioavailability 
determination, organ distributions, metabolism related to cytochrome P450 (CYP), main 
metabolites in rat urine and cross-species metabolite comparisons were all completed, with 
results indicating fast absorption, substantial organ distribution especially in the lung, heart, 
and kidney, and CYP involved metabolism profiles of antroquinonol. 
Two 7-day toxicity studies22,23 were performed in both Sprague-Dawley rats and beagle dogs 
and the maximum tolerated doses (MTD) determined were between 100 mg/kg/day for rats 
and 100 mg/kg/day for dogs. Two 28-days toxicity studies were conducted to determine no 
observed adverse effect level (NOAEL) for Sprague-Dawley rats and beagle dogs. The rat 
NOAEL was 30 mg/kg/day and the high dose of 100 mg/kg/day was not severely toxic. 
A NOAEL in the dog was not identified (i.e., loose feces, liquid feces, and vomiting were 
observed at all doses); the 30 mg/kg/day dose level was tolerated and is the highest 
non-severely toxic dose (HNSTD). 


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Toxicokinetic evaluations were performed on a 7-day dog study (100, 250, 500 mg/kg/day 
single dose, 500 mg/kg/day 3 days dose) and the two 28-day studies mentioned above 
(Rat: 10, 30, 100 mg/kg/day single and 28 days dose; Dog: 10, 30, 100 mg/kg/day single and 
28 days dose). Fast absorption of antroquinonol was repeatedly seen in rats and dogs with 
peak time (Tmax) ranging from 0.25 to 6 hours. A trend of dose proportionality in the rat and 
dog was more or less shown after 1 day of treatment. After 28 days of treatment, rat and dog 
studies showed inconsistent phenomena in dose proportionality view, one was greater and the 
other was less than linear in the dose-exposure relationship. 
No genotoxicity and no reproductive toxicity (up to 80 mg/kg/day) of antroquinonol was 
observed via Ames test, mammalian cell gene mutation test, micronucleus test, erythrocyte 
micronucleus test and in vivo study in Sprague-Dawley rats. 
As known to the sponsor, no fatal or severe/serious adverse drug reaction has been reported 
for the marketed product (food supplement) of Antrodia camphorata. 
7.4 
Clinical Study Data – Phase 1 Study  
A first-in-human phase I study was performed to determine the MTD and to evaluate PK, 
safety / tolerability and efficacy profiles of antroquinonol in NSCLC patients who are 
refractory to conventional treatment modalities. This open-label, non-randomized, 
dose-escalation study, which completed in February 2013, enrolled a total of 13 patients; 
seven males and six females, all of whom were Asian. A total of five patients were enrolled 
an accelerated titration phase (one patient each in the 50, 100, 200, 300, and 450 mg dose 
groups) and eight patients were enrolled in a standard titration phase (three patients in the 
450 mg dose group and five patients in the 600 mg dose group). 
No Dose Limiting Toxicities (DLTs) were reported in any patient for any of the doses 
(50, 100, 200, 300, 450, and 600 mg) in the Intent-to-Treat Population in the accelerated 
titration phase or standard titration phase. 
Pharmacokinetic results indicated that the rate and extent of absorption of antroquinonol 
increased in a dose proportional manner over the dosing range of 50 to 600 mg after multiple 
administrations of antroquinonol. However, the rate and extent of antroquinonol absorption 
increased in a non-dose proportional and a dose proportional manner, respectively, over the 
dosing range of 50 to 600 mg under single dose conditions. No clear trend was observed 
when comparing the PK parameters under single dose conditions to those under multiple dose 
conditions. 
Due to the limited number of patients per dose group (one patient each received 50, 100, 200, 
and 300 mg, four patients received 450 mg, and five patients received 600 mg), these results 
should be interpreted with caution. 
Efficacy results indicated that the tumor overall response at the end of treatment showed 
stable disease for all three patients included in the Per-Protocol population: one patient in the 
200 mg dose group and two patients in the 600 mg dose group (100%). 
 


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Safety results indicated that antroquinonol at 50, 100, 200, 300, 450, and 600 mg dose levels, 
given daily for 4 weeks, was generally safe and well tolerated. Antroquinonol at 50, 100, 200, 
300, 450, and 600 mg dose levels exhibited a low toxicity profile. Overall, four patients 
reported four serious adverse events (SAEs) with two patients each in the 450 and 600 mg 
dose groups. Of these, one patient from each dose group died due to progressive disease and 
discontinued from the study (one patient in the 600 mg dose group discontinued due to the 
adverse event [AE] of pleural effusion). None of the deaths, SAEs, and AEs leading to 
discontinuations was related to the study drug. No Grade 4 treatment-emergent adverse 
events (TEAEs) were reported as determined by the National Cancer Institute-Common 
Terminology Criteria for Adverse Events (NCI-CTCAE), Version 4.03.24  
Treatment-emergent AEs of toxicity Grade 3 were reported in two patients (one patient in the 
200 mg dose group experienced vertigo and one patient in the 450 mg dose group 
experienced decreased appetite and encephalitis); all events were unrelated to the study drug. 
All 13 (100%) patients treated reported TEAEs that were considered treatment-related. The 
most commonly occurring TEAEs, reported in > two patients, overall, were in the system 
organ classes of gastrointestinal disorders (12 patients, 92.3% [seven patients in Grade 1, 
53.8%, and five patients in Grade 2, 38.5%]), and by preferred term were diarrhea 
(10 patients, 76.9% [nine patients in Grade 1, 69.2%, and one patient in Grade 2, 7.7%]), 
vomiting (nine patients, 69.2% [six patients in Grade 1, 46.2%, and three patients in Grade 2, 
23.1%]), and nausea (seven patients, 53.8% [six patients in Grade 1, 46.2%, and one patient 
in Grade 2, 7.7%]). 
No patient had any laboratory abnormality recorded as a TEAE except for one case of 
hematuria of Grade 1 in the 450 mg dose group. Per the sonogram report of the kidney, 
stones sized 0.47 cm and 0.50 cm in the left kidney without hydronephrosis were noted. The 
event was considered to be unrelated to the study drug. There were slight increases or 
decreases in the hematology and biochemistry parameters but none were considered 
abnormal results. 
For urinalysis, at Cycle 1 baseline, four patients had abnormal urinalysis results: one patient 
each in the 200 and 600 mg dose groups and two patients in the 450 mg dose group. At 
follow-up, five patients had abnormal urine values: two patients in the 450 mg group that had 
abnormal values at baseline and three new patients at lower dose levels (one patient each in 
the 50, 100, and 300 mg dose groups). 
None of the patients were reported to have clinically significant changes in any of the vital 
sign, electrocardiogram (ECG), and physical examination parameters at the Follow-Up Visit. 
The Eastern Cooperative Oncology Group (ECOG) score was 1 for all patients at all time 
points, except for two patients in the 450 mg group who had an ECOG score of 4 (completely 
disabled, cannot carry on any self-care) at the Follow-Up Visit and a score of 2 (ambulatory 
and capable of all self-care but unable to carry out any work activities) at the Cycle 3, Day 28 
visit. 


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7.5 
Rationale for the Study 
Existing treatments for advanced NSCLC have not brought very satisfactory survival results 
and poor-prognosis remains for patients with advanced NSCLC. Preclinical pharmacology 
and toxicology studies, described above, have indicated that antroquinonol is a drug with 
potential lung cancer cytotoxic activity and relatively low toxicity profile. The cumulative 
exposure in humans of antroquinonol contained in Antrodia camphorata, the currently 
marketed health food supplement product, is over 7.8 million capsules, translating to 8.6 kg 
of antroquinonol for duration of approximately 4 years. Although supplied at a different dose 
unit and daily dose strength, no fatal, serious/severe drug adverse reactions have ever been 
reported to the sponsor due the marketed product. 
In the phase I study in NSCLC patients refractory to conventional treatment modalities, 
antroquinonol at 50, 100, 200, 300, 450, and 600 mg dose levels, given daily for 4 weeks, 
was generally safe and well tolerated as no particular safety concerns or DLTs were identified 
in the study. In addition, efficacy results indicated that the tumor overall response at the end 
of treatment showed stable disease for all three patients included in the per-protocol 
population: one patient in the 200 mg dose group and two patients in the 600 mg dose group 
(100%). Therefore its progression to further clinical development is warranted in a larger 
number of patients with NSCLC. 
The rationale for the study design is described in more detail in Section 9.2. 


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8 
STUDY OBJECTIVES 
8.1 
Primary Objective 
To evaluate the activity of antroquinonol in unselected, KRAS-positive, and KRAS-negative 
patients with stage IV (including pleural effusion) non-squamous NSCLC who have failed 
two lines of anti-cancer therapy. 
8.2 
Secondary Objective 
To assess the safety and tolerability and PK of antroquinonol in patients with stage IV 
(including pleural effusion) non-squamous NSCLC who have failed two lines of anti-cancer 
therapy. 
8.3 
Exploratory Objective 
To explore potential relationships between antroquinonol exposure and safety and efficacy 
endpoints. 


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9 
INVESTIGATIONAL PLAN 
9.1 
Overall Study Design and Plan 
9.1.1 
Description 
This is a single-arm, open-label, Phase II study in KRAS-positive and KRAS-negative 
patients with stage IV (including pleural effusion) non-squamous NSCLC who have failed 
two lines of anti-cancer therapy. This is defined as patients with radiologically confirmed 
disease progression following greater than or equal to two, but less than or equal to four, prior 
lines of systemic anti-cancer therapy (see Section 9.3.1 for a detailed description of the 
eligibility criteria). A maximum of 60 evaluable patients with NSCLC will receive 
antroquinonol, of which 30 patients will be KRAS-positive and 30 patients KRAS-negative. 
An evaluable patient will have received at least one dose of antroquinonol and have a valid 
baseline tumor assessment (see Section 14.2 for further details). Enrollment will continue 
until the target number of evaluable patients has been enrolled. 
Written informed consent must be obtained from all patients before initiating Screening. The 
Screening period will be up to 42 days in duration (Days -42 to -1). Following completion of 
all Screening assessments and confirmation of eligibility criteria, patients will receive 
antroquinonol 200 mg three-times-a-day (t.i.d. at 8-hour intervals) on Day 0 for 12 weeks 
(one treatment cycle) or until documented evidence of disease progression, unacceptable 
toxicity, non-compliance or withdrawal of consent by the patient, or the investigator decides 
to discontinue treatment, whichever comes first. Study drug should be taken at 8-hour 
intervals. The time of study drug administration should be recorded in the patient diary. 
After the first 12-week treatment cycle, patients who are progression-free will be eligible to 
receive further (12-week) treatment cycles with antroquinonol (Extension Phase), until 
documented evidence of disease progression, unacceptable toxicity, non-compliance or 
withdrawal of consent by the patient, or the investigator decides to discontinue treatment, 
whichever comes first. Investigators should wait at least 7 days after the last administration of 
study drug before initiating alternative treatment. 
Patients will attend study visits on Days 0, 14, 28, 42, 56 and 84 during the first 12-week 
treatment cycle, every 4 weeks during the second, third, and fourth treatment cycles 
(Extension Phase); and every 12 weeks during subsequent treatment cycles (Extension 
Phase). The study-specific procedures include: physical examination, vital signs, 12-lead 
ECG, performance status, clinical laboratory tests, AEs, concomitant medication and patient 
compliance. The schedule of assessments is presented in Table 9.1. 
Patients discontinuing study drug will attend an End of Study (EOS) Visit, 4 weeks after the 
last administration of study drug. In the event that a patient is scheduled to start a new 
treatment earlier than 3 weeks after the last dose of study drug, the EOS Visit should occur 
before the start of the new treatment and the reason documented. 
Intensive PK sampling will be performed on Days 0 and 28 in all patients enrolled in Stage 1. 
Sparse PK sampling will be performed on Days 28, 42, and 56 in all patients enrolled in 
Stage 2. 


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All patients who withdraw from the study drug, but consent to be followed up for survival 
status, will be followed up by telephone contact every 3 months, for a maximum of 6 months 
from the date of last administration of study drug or death, whichever occurs first. 
Tumor assessments will be performed at Screening, Days 42 and 84 using the Response 
Evaluation Criteria in Solid Tumors (RECIST) criteria, version 1.1 (see Appendix 1). Tumor 
assessments will be performed every 12 weeks during the Extension Phase. 
The primary efficacy endpoint is progression-free survival (PFS) rate at 12 weeks, which is 
defined as the proportion of patients alive and progression-free at Week 12. Patients will be 
progression-free if they have no evidence of progressive disease (defined according to 
RECIST guidelines, version 1.1) from the start of treatment to Week 12. 
The study uses a two-stage design seeking to detect a true PFS rate of more than 35% in the 
overall (unselected) population and 40% within the KRAS tumor mutation positive and 
negative strata. Thirty evaluable patients (15 in each stratum) will be treated initially 
(Stage 1), with expansion to a maximum of 60 evaluable patients (Stage 2). The rules for 
continuing the overall study and individual stratum are provided in Section 14.2. 
An Independent Data Monitoring Committee will act in an advisory capacity to monitor 
patient safety and efficacy data from the study. The members will be selected on the basis of 
relevant experience and understanding of clinical research and the issues specific to the 
therapeutic area, as well as previous data monitoring committee experience. 
9.1.2 
Schedule of Assessments 
The schedule of assessments is presented in Table 9.1. 
 
 


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Table 9.1 
Schedule of Study-Specific Procedures 
Study Procedure 
Screening
(-42 days) 
Visit (Day) 
End of Study 
(EOS) Visit2 
Extension 
Phase3 
1 (0) 
2 (14) 
3 (28) 
4 (42) 
5 (56) 
6 (84) 
Study visit window (days) 
N/A 
0 
± 3 
± 3 
± 3 
± 3 
± 3 
± 7 
± 7 
Informed consent1 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical & surgical history 
X 
 
 
 
 
 
 
 
 
Concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Inclusion/Exclusion criteria 
X 
 
 
 
 
 
 
 
 
Tumor biomarkers4 
X 
 
 
 
 
 
 
 
 
Physical examination5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test6 
X 
 
 
 
 
 
 
 
 
Vital signs7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG performance score 
X 
X 
 
X 
X 
X 
X 
X 
X 
12-Lead ECG 
X 
X 
 
X 
X 
X 
X 
X 
X 
Clinical laboratory tests8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Tumor assessments9 
X 
 
 
 
X 
 
X 
 X 
X 
Dispense study drug10 
 
X 
 
X 
 
X 
X 
 
X 
Drug accountability 
 
 
 
X 
X 
X 
X 
X 
X 
PK sampling11 
 
X 
 
X 
X 
X 
 
 
 
AE assessment12 
 
X 
X 
X 
X 
X 
X 
X 
X 
Patient compliance 
 
X 
X 
X 
X 
X 
X 
X 
X 


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Study Procedure 
Screening
(-42 days) 
Visit (Day) 
End of Study 
(EOS) Visit2 
Extension 
Phase3 
1 (0) 
2 (14) 
3 (28) 
4 (42) 
5 (56) 
6 (84) 
EORTC QLQ13 
 
X 
 
 
X 
 
X 
X 
X 
Overall survival14 
 
 
 
 
 
 
 
X 
 
ECOG: Eastern Cooperative Oncology Group; ECG: Electrocardiogram; PK: Pharmacokinetics; AE: Adverse Event; EORTC: European Organization for Research and 
Treatment of Cancer; QLQ: Quality of Life Questionnaire. 
1 
Informed consent must be obtained before the patient undergoes any study-specific procedures. 
2 
Patients discontinuing study will attend an EOS Visit, 4 weeks after the last administration of study drug. In the event that a patient is scheduled to start a new treatment 
earlier than 3 weeks after the last dose of study drug, the EOS Visit should occur before the start of the new treatment and the reason documented. Tumor assessment does 
not need to be performed at the EOS Visit if this was conducted at the Day 84 Visit. For patients participating in the Extension Phase, the tumor assessment does not need 
to be performed at the EOS Visit if it has been assessed within 8 weeks of the EOS Visit. 
3 
After the first 12-week treatment cycle, patients who are progression-free will be eligible to receive further (12-week) treatment cycles with antroquinonol (Extension 
Phase), until documented evidence of disease progression, unacceptable toxicity, non-compliance or withdrawal of consent by the patient, or the investigator decides to 
discontinue treatment, whichever comes first. Investigators should wait at least 7 days after the administration of study drug before initiating alternative treatment is 
administered. Patients discontinuing the study will attend an EOS Visit 4 weeks after last administration of study drug. Patients will attend visits every 4 weeks (± 7 days) 
during the second, third, and fourth treatment cycles in the Extension Phase. After completion of the fourth treatment cycle, patients will attend visits every 12 weeks 
(± 7 days). 
4 
Tumor tissue blocks or slides will be obtained from archival material or from fresh biopsy during the Screening period to determine the tumor KRAS mutation status 
before the patient is enrolled. A patient may be enrolled based on KRAS test results from the local laboratory. Pleural fluid cytology may be used to determine KRAS 
mutation status if the cytology was pathologically reviewed and reported to contain malignant cells consistent with NSCLC. Tumor tissue will also be used to study arrays 
of genomic and proteomic markers of interest. 
5 
Weight, height and body mass index (BMI) will be measured at Screening Visit only. 
6 
A urine pregnancy test will be performed during the Screening Visit for women of child-bearing potential. This test can be repeated during the study if required by local 
regulations. 
7 
Vital signs (respiratory rate, heart rate, blood pressure, and body temperature) will be performed at each visit. They will be obtained in the sitting position after the patient 
has rested for 5 minutes. The date and time of the assessment should be recorded. 
8 
Hematology, chemistry, and urinalysis. All tests performed at the Central Laboratory Facility. 
9 
Radiological and clinical tumor assessments will be performed at Screening, Day 42 and Day 84 using the RECIST criteria version 1.1. Evaluation during Screening must 
be performed within 14 (± 7) days of the date of first administration of study drug. Tumor assessments will be performed every 12 weeks during the Extension Phase. 
10 All Screening procedures and laboratory results must be available and reviewed before the patient receives the first dose of study drug. Study drug should be taken at 8-
hour intervals. The time of study drug administration should be recorded in the patient diary. 
11 Intensive PK sampling will be performed on Days 0 and 28 in all patients enrolled in Stage 1. Samples will be taken 30 minutes prior to and 0.5, 1, 2, 3, 4, 6, and 8 hours 
after the first dose on Day 0, and immediately before and 0.5, 1, 2, 3, 4, 6, and 8 hours after the first dose on Day 28. Sparse PK sampling will be performed on Days 28, 
42, and 56 in all patients enrolled in Stage 2. At least two samples will be collected on each occasion, one of which will be a trough concentration (30 minutes prior to 


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dosing and approximately 8 hours after the last dose on the prior day). At least one sample per patient will be timed to coincide with the peak concentration 
(approximately 3 hours after dosing). The remainder may be taken at any time during the dosing interval. 
12 Patients must be followed for AEs from the date of informed consent until resolution or stabilization,  alternative treatment for NSCLC is started, 6 months after last dose 
of study drug, or loss to follow-up, whichever occurs first. In the event of serious or study drug-related toxicities, the patient will be followed until resolution or 
stabilization. Safety follow-up data may be collected by telephone contact every 3 months after the EOS Visit. 
13 Day 0 evaluation to be performed before the patient receives the first dose of study drug. 
14 All patients who withdraw from the study drug, but consent to be followed up for survival status, will be followed up by telephone contact every 3 months, for a 
maximum of 6 months from the date of last administration of study drug or death, whichever occurs first.. 
 


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The schedule of blood samples that will be drawn for each patient is presented in Table 9.2. 
Table 9.2 
Schedule of Blood Sampling 
Day  Sample 
No.  
Time Schedule 
(hour)  
Time* 
(hhmm)  
Time 
Window  Activity  
Stage 1 
0  
N/A  
-1  
0700  
 
Patient registration  
0  
N/A  
-0.5  
0730  
 
Take blood for laboratory test  
0  
1  
-0.5  
0730  
 
Take pre-dose sample  
0 
N/A 
-0.25 
0745 
 
Take meal or light snack 
0  
N/A  
0  
0800  
 
Take dose  
0  
2  
0.5  
0830  
± 5 min  
 
0  
3  
1  
0900  
± 10 min   
0  
4  
2  
1000  
± 15 min   
0  
5  
3  
1100  
± 20 min   
0  
6  
4  
1200  
± 20 min   
0  
7 
6  
1400  
± 20 min   
0  
8  
8  
1600  
± 20 min   
28  
N/A  
-1  
0700  
 
Patient registration  
28  
N/A  
-0.5  
0730  
 
Take blood for laboratory test  
28 
9 
-0.5** 
0730 
 
Take pre-dose sample 
28  
N/A  
-0.25 
0745  
 
Take meal or light snack 
28  
N/A 
0  
0800  
 
Take dose  
28  
10 
0.5  
0830  
± 5 min  
 
28  
11 
1  
0900  
± 10 min   
28  
12 
2  
1000  
± 15 min   
28  
13 
3  
1100  
± 20 min   
28  
14 
4  
1200  
± 20 min   
28  
15 
6  
1400  
± 20 min   
28  
16 
8  
1600  
± 20 min   
Stage 2 
28  
1 
-0.5** 
N/A  
 
Trough  
28  
2 
3 
N/A 
± 1 hr  
Peak 
42 
3 
-0.5** 
N/A  
 
Trough 
42 
4 
N/A 
N/A 
 
Random*** 
56 
5 
-0.5** 
N/A  
 
Trough 
56 
6 
N/A 
N/A 
 
Random*** 
* Provided for guidance in scheduling the sampling timing for the visits; the time windows must be followed. 
** Sample should be taken approximately 8 hours after the prior dose. 
*** Sample may be taken at any time during the dosing interval. 


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9.1.3 
Study Procedures 
9.1.3.1 
Screening (up to 42 days before Day 0)  
• Explain the nature of the study and have patients to read and sign an Informed Consent 
Form (ICF) 
• Assign patient identifier (Screening number) to patients  
• Obtain demographic characteristics 
• Record medical and surgical history including cancer history  
• Record medication history including cancer treatment history 
• Screen patients for inclusion/exclusion criteria. 
• Obtain a tissue sample (tumor biopsy or archived tumor tissue) to determine KRAS tumor 
mutation status prior to study enrollment. A patient may be enrolled based on KRAS test 
results from the local laboratory. Pleural fluid cytology may be used to determine KRAS 
mutation status if the cytology was pathologically reviewed and reported to contain 
malignant cells consistent with NSCLC. Tumor tissue from patients will also be used to 
evaluate arrays of genomic and proteomic markers of interest. 
• Perform physical examinations. Weight, height and body mass index (BMI) will be 
measured at Screening Visit only   
• Perform urine pregnancy test for applicable patients only. A urine pregnancy test will be 
performed during the Screening Visit for women of child-bearing potential. This test can 
be repeated during the study if required by local regulations 
• Obtain vital signs. Vital signs (respiratory rate, heart rate, blood pressure, and body 
temperature) will be obtained in the sitting position after the patient has rested for 
5 minutes. The date and time of the assessment should be recorded. 
• Perform ECOG performance status evaluation (see Appendix 2)  
• Perform 12-Lead ECG examinations  
• Perform clinical laboratory tests (hematology, biochemistry, and urinalysis) 
• Tumor assessments (radiological and clinical tumor assessments). Evaluation at the 
Screening Visit must be performed within 14 (± 7) days of the date of first administration 
of study drug. 
9.1.3.2 
Visit 1 (Day 0) 
• Record concomitant medications 
• Perform physical examinations  
• Obtain vital signs  
• Perform ECOG performance status evaluation 
• Perform 12-Lead ECG examinations  


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• Perform clinical laboratory tests (hematology, biochemistry, and urinalysis) 
• Dispense study drug. All Screening procedures, laboratory results and repeat laboratory 
results must be available and reviewed before the patient receives the first dose of study 
drug  
• Collect pre-dose blood sample within 30 minutes prior to dosing (Stage 1 only) 
• Administer the first dose of study drug at site and collect PK blood samples 0.5, 1, 2, 3, 4, 
6, and 8 hours after dosing (Stage 1 only) 
• Document study drug dosing time 
• Record AE and grade possible toxicity  
• Calculate patient compliance 
• Perform European Organization for Research and Treatment of Cancer (EORTC) Quality 
of Life Questionnaires (QLQ) (see Appendix 3) 
9.1.3.3 
Visit 2 (Day 14 ± 3) 
• Record concomitant medications 
• Perform physical examinations 
• Obtain vital signs 
• Perform clinical laboratory tests (hematology, biochemistry, and urinalysis) 
• Record AE and grade possible toxicity 
• Calculate patient compliance 
9.1.3.4 
Visit 3 (Day 28 ± 3) 
• Record concomitant medications 
• Perform physical examinations  
• Obtain vital signs  
• Perform ECOG performance status evaluation 
• Perform 12-Lead ECG examinations  
• Perform clinical laboratory tests (hematology, biochemistry, and urinalysis) 
• Dispense study drug 
• Perform drug accountability  
• Collect pre-dose blood sample 30 minutes prior to dosing (Stage 1 and 2; approximately 
8 hours after the prior dose) 
• Administer study drug at site and collect PK blood samples 0.5, 1, 2, 3, 4, 6, and 8 hours 
after dose (Stage 1 only). Stage 2 only: collect PK blood sample 3 hours after dose 
• Document study drug dosing time 


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• Record AE and grade possible toxicity  
• Calculate patient compliance 
9.1.3.5 
Visit 4 (Day 42 ± 3) 
• Record concomitant medications 
• Perform physical examinations  
• Obtain vital signs  
• Perform ECOG performance status evaluation 
• Perform 12-Lead ECG examinations  
• Perform clinical laboratory tests (hematology, biochemistry, and urinalysis) 
• Tumor assessments (radiological and clinical tumor assessments) 
• Perform drug accountability  
• Collect pre-dose blood sample 30 minutes prior to dosing (Stage 2 only; approximately 
8 hours after the prior dose) 
• Administer study drug at site and collect random PK blood sample (Stage 2 only) 
• Record AE and grade possible toxicity  
• Calculate patient compliance 
• Perform EORTC QLQ  
9.1.3.6 
Visit 5 (Day 56 ± 3) 
• Record concomitant medications 
• Perform physical examinations  
• Obtain vital signs  
• Perform ECOG performance status evaluation 
• Perform 12-Lead ECG examinations  
• Perform clinical laboratory tests (hematology, biochemistry, and urinalysis) 
• Dispense study drug 
• Perform drug accountability  
• Collect pre-dose blood sample 30 minutes prior to dosing (Stage 2 only; approximately 
8 hours after the prior dose) 
• Administer study drug at site and collect random PK blood sample (Stage 2 only) 
• Record AE and grade possible toxicity  
• Calculate patient compliance 


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9.1.3.7 
Visit 6 (Day 84 ± 3) 
• Record concomitant medications 
• Perform physical examinations  
• Obtain vital signs  
• Perform ECOG performance status evaluation 
• Perform 12-Lead ECG examinations  
• Perform clinical laboratory tests (hematology, biochemistry, and urinalysis) 
• Tumor assessments (radiological and clinical tumor assessments) 
• Dispense study drug 
• Perform drug accountability  
• Record AE and grade possible toxicity  
• Calculate patient compliance 
• Perform EORTC QLQ 
9.1.3.8 
End of Study (EOS) Visit (± 7 days) 
Patients will attend an EOS Visit, 4 weeks after the last administration of study drug. In the 
event that a patient is scheduled to start a new treatment earlier than 3 weeks after the last 
dose of study drug, the EOS Visit should occur before the start of the new treatment and the 
reason documented. 
• Record concomitant medications 
• Perform physical examinations  
• Obtain vital signs  
• Perform ECOG performance status evaluation 
• Perform 12-Lead ECG examinations  
• Perform clinical laboratory tests (hematology, biochemistry, and urinalysis) 
• Tumor assessments (radiological and clinical tumor assessments). Tumor assessment does 
not need to be performed at the EOS Visit if this was conducted at the Day 84 Visit. For 
patients participating in the Extension Phase, the tumor assessment does not need to be 
performed at the EOS Visit if it has been assessed within 8 weeks of the EOS Visit. 
• Perform drug accountability  
• Record AE and grade possible toxicity. Safety follow-up data may be collected by 
telephone contact every 3 months after the EOS Visit. 
• Calculate patient compliance 
• Perform EORTC QLQ 


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• All patients who withdraw from the study drug, but consent to be followed up for survival 
status, will be followed up by telephone contact every 3 months, for a maximum of 
6 months from the date of last administration of study drug or death, whichever occurs 
first. 
9.1.3.9 
Extension Phase Visits (± 7 days) 
Patients will attend visits every 4 weeks (± 7 days) during the second, third, and fourth 
treatment cycles. After completion of the fourth treatment cycle, patients will attend visits 
every 12 weeks (± 7 days). 
• Record concomitant medications 
• Perform physical examinations  
• Obtain vital signs  
• Perform ECOG performance status evaluation 
• Perform 12-Lead ECG examinations  
• Perform clinical laboratory tests (hematology, biochemistry, and urinalysis) 
• Tumor assessments (radiological and clinical tumor assessments) 
• Dispense study drug 
• Perform drug accountability  
• Record AE and grade possible toxicity  
• Calculate patient compliance 
• Perform EORTC QLQ 
9.2 
Discussion of Study Design 
9.2.1 
Rationale for Single-Arm, Open-Label Phase II Study  
This is a single-arm, open-label, Phase II study in KRAS-positive and KRAS-negative 
patients with stage IV (including pleural effusion) non-squamous NSCLC who have failed 
two lines of anti-cancer therapy. This is defined as patients with radiologically confirmed 
disease progression following greater than or equal to two, but less than or equal to four, prior 
lines of systemic anti-cancer therapy (see Section 9.3.1 for a detailed description of the 
eligibility criteria). The rationale for this study is outlined in Section 7.5 and described in 
more detail below. 
The subject population of patients with stage IV (including pleural effusion) non-squamous 
NSCLC who have failed two lines of anti-cancer therapy was chosen for this study as there is 
a current unmet need to treat this population and results from the first-in-man Phase 1 study 
indicate that the tumor overall response at the end of treatment showed stable disease for all 
three patients (one patient in the 200 mg dose group and two patients in the 600 mg dose 
group) included in the per-protocol set (PPS). The PPS was defined in the Phase 1 study as all 
patients who completed at least three cycles of treatment with proper imaging assessment 


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(RECIST v.1.1). Furthermore, antroquinonol at 50, 100, 200, 300, 450, and 600 mg dose 
levels, given daily for 4 weeks, was generally safe and well tolerated, with no particular 
safety concerns or DLT being identified in the study. 
Preclinical data (see Section 7.3) suggest that patients with KRAS mutation positive tumors 
may derive greater benefit from antroquinonol therapy. Hence, patients will be stratified 
according to KRAS mutation status. 
An open-label design was selected as this was considered the most suitable design for 
evaluation of antroquinonol as a single agent in the patient population eligible for 
participation in this study. 
A two-stage, single-arm design was chosen as this was considered most suitable for assessing 
the safety, tolerability, PK and efficacy of antroquinonol in patients who have previously 
failed two lines of anti-cancer therapy. 
Antroquinonol will be administered as a single agent in this study at a dose of 600 mg per day 
(200 mg t.i.d. administered at 8-hour intervals). This dose regimen was chosen based on 
results from the Phase 1 clinical study (GOLANTA20090911) involving NSCLC patients 
refractory to conventional treatment modalities, which reported good tolerability of 
antroquinonol up to 600 mg/day. The area under the plasma concentration-time curve from 
0 to 24 hours (AUC0-24) after single dose administration on Day 1 of the first treatment cycle 
(Cycle 1) increased by 18.79%, 200.1%, 215.16%, 265.19% and 396.61% at the 100, 200, 
300, 450, and 600 mg dose levels, respectively, when compared with the 50 mg dose level; 
whereas on Day 28 of Cycle 1, the AUC0-24 decreased by 34.88% at the 100 mg dose level 
and increased by 133.58%, 141.87%, 680.65% and 562.54% at the 200, 300, 450, and 
600 mg dose levels, respectively. Thus, the AUC0-24 was not linearly proportional to the 
antroquinonol dose on Day 1 and Day 28. There were no significant differences in AUC0-24 in 
the 100-300 mg dose range on Day 1 and Day 28. The highest peak concentration (Cmax) over 
the 100-300 mg dose range was observed with the 200 mg dose on Day 28. One patient in the 
200 mg dose group and two patients in the 600 mg dose group exhibited stable disease at the 
end of treatment. 
Thus, in order to maintain a high drug concentration and enhance the efficacy of 
antroquinonol 200 mg t.i.d. (every eight hours) has been chosen as the dosage regimen for 
this study. 
The study design is based on the assumption that within each of the KRAS tumor mutation 
positive and negative strata, a PFS rate at 12 weeks of 40% and 35% overall would be of 
interest. Further testing would not be pursued if the PFS rate at 12 weeks was less than 15%. 
See Section 14.1 for further details. 
The study drug will be administered until disease progression, occurrence of unacceptable 
toxicity, non-compliance or withdrawal of consent by the patient, or investigator decision to 
stop study drug, whichever comes first. 


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9.2.2 
Appropriateness of Measurements 
The primary efficacy endpoint in this study is the PFS rate, defined as the proportion of 
patients alive and progression-free at Week 12. Patients will be progression-free if they have 
no evidence of progressive disease (per RECIST version 1.1) from the start of treatment to 
Week 12. The RECIST guidelines recognize that the proportion progression-free at a 
pre-specified time point is an appropriate to assess the anti-tumor activity of agents such as 
antroquinonol, where biological activity is more likely to translate into stabilization of 
disease.25  
Tumor response, based on radiological measurement, is a standard and well accepted efficacy 
endpoint in clinical development. Response to study drug will be assessed in this study using 
RECIST version 1.1 (see Appendix 1), an internationally standardized and widely accepted 
standard for measuring response to treatment in cancer.25 
The secondary efficacy measures of objective response rate (ORR), disease control rate 
(DCR), duration of overall tumor response (DR), PFS, overall survival (OS) and time to 
progression (TTP) are also well accepted efficacy endpoints in clinical development for 
oncology studies and in line with recommendations in the European Medicine’s Agency 
(EMA), Committee for Medicinal Products for Human Use (CHMP) Guideline on the 
Evaluation of Anticancer Medicinal Products in Man (EMA/CPMP/205/95/Rev.4, 2012)26; 
and the United States (US) Food and Drug Administration (FDA) Guidance for Industry on 
Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics (US Department of 
Health and Human Services, May 2007).27  
The safety and PK endpoints in this study are standard and well understood endpoints in 
clinical oncology. The corrected QT (QTc) assessment strategy for this study is based on 
recommendations in the International Conference on Harmonisation (ICH) E14 guideline28 
and is designed to focus on the collection of cardiac safety information. There are no 
concerns for cardiotoxicity based on the mechanism of action, the nonclinical toxicology 
studies, or the limited clinical information available to date. Twelve-lead ECGs are required 
during Screening, during treatment, and at the End of Treatment Visit, and as clinically 
indicated. 
Quality of life will be assessed using EORTC QLQ C30 (QLQ-C30) and the Module on Lung 
Cancer (QLQ-LC13), which is a validated instrument for assessing quality of life (QoL) in 
patients with lung cancer. 
The EORTC QLQ-C30 / EORTC QLQ-LC13 is comprised of a global health status scale, 
five functional scales (physical, role, emotional, cognitive, and social), three symptom scales 
(fatigue, nausea and vomiting, and pain), and several single items, as well as a module 
designed specifically for lung cancer. These QoL assessment tools are included in this study 
in order to evaluate the side effects of antroquinonol as well as the impact of treatment on 
patients’ disease-related symptoms. 


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9.2.3 
Risk/Benefit and Ethical Assessment 
As known to the sponsor, no fatal or severe/serious adverse drug reaction has been reported 
by the marketed product (food supplement) of Antrodia camphorata. 
Patients anticipated to be enrolled into the study will be non-squamous NSCLC patients with 
confirmed disease progression following two prior lines of systemic anti-cancer therapy for 
recurrent/metastatic disease (one of which should be a platinum-based regimen). As the dose 
utilized for this study is considered conservative and acceptable, and the patients targeted are 
mainly patients with rather limited treatment options, the risk and benefit assessment is 
deemed justifiable. 
9.2.4 
Early Termination 
This study may be terminated at the discretion of the sponsor or any regulatory agency. A 
principal investigator (PI) may elect to discontinue or stop the study at his or her site for any 
reason including safety or low enrollment. 
9.3 
Selection of Study Population 
9.3.1 
Inclusion Criteria 
Patients eligible for enrollment in the study must meet all of the following criteria: 
1. Cytologically or histologically confirmed non-squamous NSCLC Stage IV (including 
pleural effusion) 
2. Radiologically confirmed disease progression following greater than or equal to two, but 
less than or equal to four, prior lines of systemic anti-cancer therapy, one of which should 
be a platinum-based regimen, OR the patient has refused treatment with approved 
treatment modalities, OR the investigator feels that the patient is not a candidate for other 
systemic therapy. Patients with epidermal growth factor receptor (EGFR)-positive 
mutations should have been offered treatment with an EGFR-TK inhibitor prior to 
enrolment in this study. Adjuvant therapy with or without maintenance therapy would 
count as one line of systemic therapy. A line of therapy requires at least two 3-4 week 
complete cycles unless it was stopped due to toxicity, in which case it would count as one 
line of therapy 
3. At least one radiologically measurable target lesion per RECIST version 1.1 
4. Fresh or archival biopsy tissue available to determine KRAS tumor mutation status 
5. At least 18 years of age at the time of signing informed consent 
6. Life expectancy of at least 3 months 
7. Written informed consent that is consistent with ICH Tripartite Guideline on Good 
Clinical Practice (GCP) guidelines 
8. Patient or legally acceptable representative has granted written informed consent before 
any study-specific procedures (including special Screening tests) are performed 
9. Eastern Cooperative Oncology Group (ECOG) performance score of 0, 1 or 2 


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10. Hemoglobin ≥ 9.0 g/dL; platelets ≥ 100 x 109/L; ANC ≥ 1.5 x 109/L without the use of 
hematopoietic growth factors 
11. Bilirubin and creatinine less than 2 × upper limit of normal (ULN) for the institution 
12. Albumin ≥ 2.5 g/dL 
13. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than 5 × ULN 
for the institution 
14. Prothrombin time less than 1.5 × ULN for the institution 
15. Potassium, magnesium and phosphorus within the normal range for the institution 
(supplementation is permissible) 
16. Willing to use two medically accepted and effective methods of contraception from the 
list below during the study (both men and women as appropriate) and for 3 months after 
the last dose of study drug: 
− Established use of oral, injected or implanted hormonal methods of contraception. 
− Placement of an intrauterine device or intrauterine system. 
− Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/suppository. 
− Male sterilization (with the appropriate post-vasectomy documentation of the absence 
of sperm in the ejaculate). 
− True abstinence: When this is in line with the preferred and usual lifestyle of the 
patient. 
17. Recovery to ≤ Grade 1 or baseline of any toxicities due to prior treatments, excluding 
alopecia 
9.3.2 
Exclusion Criteria 
Patients meeting any of the following criteria must not be enrolled in the study: 
1. Chemo-, hormone- or immunotherapy, within 4 weeks or within less than four half-lives 
of the date of first administration of study drug and/or persistence of toxicities of prior 
anti-cancer therapies which are deemed to be clinically relevant 
2. Radiotherapy within the past 2 weeks prior to the date of first administration of study 
drug. 
3. Previous treatment with a histone deacetylase (HDAC) inhibitor or an EGFR inhibitor 
within at least 4 weeks of the date of first administration of study drug 
4. Treatment with any drug(s) known to be a strong inhibitor or inducer of CYP2C19, 
CYP3A4, CYP2C8, and CYP2E1, within 14 days of the date of first administration of 
study drug 


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5. Brain metastases which are symptomatic; patients with treated brain metastases are 
eligible with stable brain disease for at least 4 weeks without the requirement for steroids 
or anti-epileptic therapy 
6. Inability to swallow oral medications or a recent acute gastrointestinal disorder with 
diarrhea e.g., Crohn’s disease, malabsorption, or Common Terminology Criteria for 
Adverse Events (CTCAE) Grade > 2 diarrhea of any etiology at baseline 
7. Other malignancies diagnosed within the past 5 years (other than curatively treated 
cervical cancer in situ, non-melanoma skin cancer, superficial bladder tumors Ta 
[non-invasive tumor] and TIS [carcinoma in situ], or non-metastatic prostate cancer 
stage 1 to 2, which has been previously treated with surgery or radiation therapy, and 
serum prostate-specific antigen is within normal limits [test performed within the past 
12 months prior to the date of first administration of study drug]) 
8. Patients with any serious active infection (i.e., requiring an intravenous antibiotic, 
antifungal, or antiviral agent) 
9. Patients with known HIV, active hepatitis B or active hepatitis C 
10. Patients who have any other life-threatening illness or organ system dysfunction, which in 
the opinion of the investigator, would either compromise patient safety or interfere with 
the evaluation of the safety of the study drug 
11. Known or suspected substance abuse or alcohol abuse 
12. Women of child-bearing potential or men who are able to father a child unwilling to use 
two medically accepted and effective methods of contraception during the study (as 
specified in the inclusion criteria) 
13. Pregnancy or breast feeding 
14. Patient unable to comply with the protocol 
15. History of clinically significant or uncontrolled cardiac disease, including congestive 
heart failure, angina, myocardial infarction, arrhythmia, including New York Heart 
Association functional classification of 3 
9.3.3 
Removal of Patients from Study or from Study Treatment 
Patients may withdraw their consent to participate in the study and investigators may 
withdraw patients at any time without prejudice. Patients will be withdrawn from the study or 
study treatment if any of the conditions set below has occurred: 
1. Documented disease progression according to the response criteria  
2. Unacceptable toxicity 
3. Patient decides to withdraw his/her informed consent 
4. Investigator considers that the patient is no longer physically and/or psychologically able 
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5. Patient has developed a condition that requires treatment with a medication prohibited by 
the protocol 
6. Patient develops adverse effects that the investigator considers a permanent cessation of 
the study drug is necessary 
7. Non-compliance with study drug, protocol requirements, or study-related procedures 
8. Patient’s treatment is interrupted for more than 1 week and the investigator and Medical 
Monitor considers a permanent cessation of the study drug is necessary  
The investigators should complete the evaluation items for the EOS Visit upon a patient’s 
withdrawal. Tumor assessment does not need to be performed at the EOS Visit if this was 
conducted at the Day 84 Visit. For patients participating in the Extension Phase, the tumor 
assessment does not need to be performed at the EOS Visit if it has been assessed within 
8 weeks of the EOS Visit. This does not include a patient who has not been treated by the 
study drug, such as withdrawal at Screening or at Baseline. Only the electronic Case Report 
Form (eCRF) required data should be completed. All patients who are withdrawn or removed 
will not be replaced in this study. 
9.3.4 
Follow-Up for Drug Discontinuation/Patient Withdrawal from Study 
If a patient discontinues study drug and is withdrawn from the study for any reason, the study 
center must immediately notify the monitor. The date and the reason for study drug 
discontinuation or patient withdrawal from the study must be recorded on the eCRF. Patients 
who withdraw from the study are to complete all evaluations for the EOS Visit. If the PI is 
unable to complete the visit assessments, the reason(s) must be recorded in the eCRF. 


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10 
TREATMENT OF PATIENTS 
10.1 
Study Drug Treatment and Dosing  
Antroquinonol should be taken every 8 hours approximately 15 minutes after a meal or light 
snack and not within ± 1 hour of drinking an ethanol-containing beverage e.g. an alcoholic 
drink. 
Subjects who forget or are unable to take a dose at the scheduled time should be instructed to 
take the dose as soon as possible. If they do not remember or are unable to take the dose prior 
to the next scheduled dose, they should take the scheduled dose and the missed dose will not 
be made up. 
The date and time of each study drug administration should be recorded in the patient diary. 
10.2 
Treatment for Study Drug Overdose 
Treatment of study drug overdose is at the discretion of the investigator. 
10.3 
Administration on Pharmacokinetic Sampling Days 
On the days in Stage 1 when PK sampling will be performed, namely, Days 0 and 28, patients 
will eat a meal at the study site and then take their next dose of antroquinonol 15 minutes 
(± 3 minutes) after completion. Patients should take their last dose of antroquinonol on 
Day 27, approximately 8 hours before the scheduled time of dosing at the study site. 
Study drug should be taken at 8-hour intervals, approximately 15 minutes after a meal or light 
snack, and not within ± 1 hour of drinking an ethanol-containing beverage, e.g. an alcoholic 
drink. The exact time of study drug administration should be recorded in the patient diary. All 
capsules must be swallowed within 2 to 3 minutes. On Days 0 and 28 patients will remain at 
the site for 8 hours after study drug administration if required for PK. 
On days of PK sampling in Stage 2, namely, Days 28, 42, and 56, patients will eat a meal at 
the study site and then take their next dose of antroquinonol 15 minutes (± 3 minutes) after 
completion. Patients should take their last dose of antroquinonol on Days 27, 41, and 55 
approximately 8 hours before the scheduled time of dosing at the study site. 
10.4 
Extension Phase 
After the first 12-week treatment cycle, patients who are progression-free will be eligible to 
receive further (12-week) treatment cycles with antroquinonol in the Extension Phase. 
Patients participating in the Extension Phase will follow a schedule similar to that of the first 
12-week treatment cycle, except no PK samples will be drawn. Patients will attend visits 
every 4 weeks (± 7 days) during the second, third, and fourth treatment cycles. After 
completion of the fourth treatment cycle, patients will attend visits every 12 weeks 
(± 7 days). 
Patients may continue in the Extension Phase until documented evidence of disease 
progression, unacceptable toxicity, non-compliance or withdrawal of consent by the patient, 
or the investigator decides to discontinue treatment, whichever comes first. 


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If there is Grade 3 or 4 toxicity, the patient’s dose will drop down to the next lower dose 
according to the Dose Modification and Toxicity Management Guidelines in Section 10.5.  
10.5 
Dose Modification 
The guidelines for dose modification and management of drug toxicity are as follows: 
Table 10.1 
Dose Modification and Management of Drug Toxicity Guidelines  
Event  
Grade  
Management/Action  
All non-hematologic and 
hematologic adverse events that 
are study drug-related  
1 or 2  
No change.  
3  
Suspend treatment. Treatment may resume if 
toxicity is resolved to grade ≤ 1 or returns to 
baseline within 7 days. Treatment should 
resume at a reduced dose (100 mg t.i.d). 
If toxicity lasts more than 7 days, study drug 
will be permanently discontinued (subject to 
investigator and Medical Monitor 
agreement); if a patient experiences another 
grade ≥ 3 toxicity at the reduced dose, then 
study drug will be permanently 
discontinued.  
4  
Treatment may be withheld for up to 7 days due to study drug-related toxicities. Patients will 
be permanently discontinued from the study drug if treatment interruption is more than 7 days 
and the investigator and Medical Monitor consider that permanent cessation of study drug is 
necessary. If a patient resumes treatment before the end of a cycle, the patient will have to 
complete the rest of the treatment of that cycle. 
When patients are suspected to experience Grade 3 or more AEs, they should contact the site 
as soon as possible for an appointment and bring back any unused study drug to the site. 
Treatment should only be withheld for nausea, vomiting, and diarrhea of Grade ≥ 3 if 
symptoms remain at Grade ≥ 3 despite adequate treatment. If dose modification is deemed 
necessary, the unused study drug will be retrieved and a new bottle with quantity of study 
drugs calculated based on the modified dose will be dispensed. Sufficient study drug should 
be dispensed for the period from the day of dose modification to the next dispensing visit. 
The quantity given will be recorded in the eCRF and the drug accountability log. At the time 
the patient returns the unused study drug, they will be counted at the site and recorded in the 
eCRF. The dates and durations of any dosing interruptions will be recorded in the eCRF. 
10.6 
Packaging and Labeling 
The study drug for this study will be supplied by Golden Biotechnology Corporation for 
active ingredient and for final formulation and packaging. The physicochemical properties 
and the pharmaceutical specifications of the study drug for this study are provided in the 
Investigator’s Brochure.29 The sponsor is responsible for shipping the study drug to the study 
site and implementing strict inventory control for drug accountability. 
The study drug will be filled in # 2 capsules (100 mg) and then packed in a light-protected 
polyethylene bottle and closed with a piece of polyethylene cap liner fitted in the cap for each 


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dispensation at Visit 1 ( Day 0), 3 (Day 28), 4 (Day 42), 5 (Day 56) and 6 (Day 84), and 
subsequent visits for patients entering the Extension Phase. The study drug will be labeled in 
accordance with country-specific requirements. 
10.7 
Dispensing and Return of Study Drug 
The study investigator and/or the designated pharmacist will be in charge of the management 
and dispensation of the study drug. All unused study drug must be returned to investigator at 
each visit. Drug accountability and inventory will be recorded in the eCRFs and the relevant 
study log. 
Patients who participate in the Extension Phase will be given enough study drugs for one 
cycle. Study drug will be returned to the pharmacy if the patient discontinues study drug 
early. 
10.8 
Storage and Reconciliation of Supplies 
The available stability data supports a 3-year shelf-life for antroquinonol capsules when 
stored below 28ºC and in the original package. 
Antroquinonol capsules are packaged in a light-protected polyethylene bottle. Investigational 
drug must be stored at the study site in a dry place below 28ºC and protected from direct light 
and excessive humidity, as stated in the Investigator’s Brochure.29 Antroquinonol will be 
shipped to the study site by Golden Biotechnology Corporation by express delivery. During 
shipping, the study drug will be packaged to maintain the temperature below 28 ºC. 
Patients will be instructed to store the drug at room temperature and to protect the study drug 
from light and excess humidity. 
10.9 
Concomitant Medications 
The investigators may prescribe additional medications during the study, as long as these are 
not prohibited by the protocol (Section 10.10). 
Any use of concomitant treatment must be recorded on the eCRF. 
10.10 
Prohibited Medications, Foods and Tobacco Use 
Except for antroquinonol, no other cytotoxic agents (examples listed in next paragraph), 
investigational drugs, active or passive immunotherapy, chemotherapy, and radiotherapy will 
be permitted during the study period. Simultaneous participation in other clinical treatment 
study protocols is not allowed. 
1. Small molecule inhibitors of the tyrosine kinase of EGFR, e.g., gefitinib or erlotinib  
2. Monoclonal antibody binding specifically to EGFR, e.g., cetuximab or panitumumab  
3. Recombinant humanized monoclonal antibody targeting vascular endothelial growth 
factor, e.g., bevacizumab  
4. Folate analogue metabolic inhibitor, e.g., pemetrexed 
Levonorgestrel will be prohibited during the conduction of this study because it is used as 
internal standard in bioanalysis. 


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Drugs/articles known to be strong inhibitors or inducers of CYP2C19, 3A4, 2C8, and 2E1 are 
prohibited. Drugs with a narrow therapeutic index that are substrates of 1A2, 2B6, 2C8, 2C9, 
2C19, 3A and 2D6 are also prohibited. A list of commonly known substrates, inhibitors and 
inducers is given in Appendix 4. It should be noted that this is not an exhaustive list. 
Foods which may affect the assessment of the study drug should be prohibited during the 
study. These foods include charbroiled food, star fruit, and grapefruit juice. Smoking is also 
prohibited during the study. 
10.11 
Treatment Compliance 
A patient’s treatment compliance will be assessed by the following formulae: 
For each visit, except Visit 2, the compliance will be calculated: 
[(Capsules actually used) ÷ (number of days patients exposed to study drug * planned number 
of capsules per day)] 
The number of days patients exposed to study drug is calculated as: 
[Day of last dose -Day of first dose + 1]  
Patients who undergo dose modifications will have their treatment compliance calculated by 
this formula: 
(Original dose [(Capsules actually used) ÷ (number of days patients exposed to study drug* 
planned number of capsules per day for each day patient was on original dose)]) + (Modified 
Dose [(Capsules actually used) ÷ (number of days patients exposed to study drug* planned 
number of capsules per day for each day patient was on modified dose)])  
Site staff will record compliance of patients with their assigned regimen. Patients are to be 
instructed to bring their partially used or empty bottles back for inspection at each study visit. 
All patients are to be reminded of the importance of compliance with their assigned regimen 
with an emphasis on taking their study drug on schedule (i.e., every 8 hours), and contacting 
the site for an appointment as soon as possible if they think they are experiencing significant 
toxicity. 


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11 
ASSESSMENT OF EFFICACY 
The primary and secondary efficacy analyses will be based on the independent centralized 
assessment of medical images. A detailed description of the process is provided in the 
Independent Review Charter. 
11.1 
Efficacy Variables 
Primary endpoint 
The primary endpoint is the PFS rate at 12 weeks, defined as the proportion of patients alive 
and progression-free at Week 12. Patients will be progression-free if they have no evidence 
of progressive disease (defined according to RECIST guidelines, version 1.1) from the start 
of treatment to Week 12. 
Tumor response will be assessed at 6-week intervals during the first treatment cycle using the 
RECIST criteria version 1.1. Each patient will be assigned one of the following categories: 
1) complete response (CR), 2) partial response (PR), 3) stable disease (SD), or 4) progressive 
disease (PD). Patients who died from any cause or discontinued the study for any reason 
without a post-screening or Week 12 tumor assessment will be considered as failing to 
respond to treatment. 
Secondary efficacy endpoints 
Secondary efficacy endpoints are as follows: 
• Objective response rate, defined as the proportion of patients whose best overall response 
is either CR or PR according to RECIST version 1.1. The best overall response is the best 
response recorded during the first 12-week treatment cycle. 
• Disease control rate, defined as the proportion of patients with a documented CR, PR and 
SD during the first 12-week treatment cycle according to RECIST version 1.1. 
• Duration of overall tumor response, defined as the interval between the date of the first 
observation of tumor response (CR or PR) and the date of disease progression or death. 
• Progression free survival, defined as the time from the date of first administration of 
study drug to objective tumor progression by RECIST version 1.1 or death due to any 
cause, whichever occurs first. 
• Overall survival, defined as the time from the date of first administration of study drug to 
death from any cause. 
• Time to progression, defined as the time from the date of first administration of study 
drug to objective tumor progression by RECIST version 1.1. 
Patient Reported Outcome endpoint: 
The PRO endpoint is as follows: 
• European Organization for Research and Treatment of Cancer QLQ-C30 and the EORTC 
QLQ-LC13. 


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Pharmacokinetic endpoints: 
For Stage 1, PK endpoints will be derived for intensively sampled PK profiles by 
non-compartmental methods and include: 
• Cmax: peak concentration 
• Ctrough: trough plasma concentration 
• Tmax: peak time 
• AUCτ: area under the plasma concentration-time curve over the 8-hour dosing interval 
• T½: terminal half-life 
• Vz/F: apparent volume of distribution during elimination 
• CL/F: apparent oral clearance 
• T½, eff: effective half-life 
If possible, PK data from all patients will be analyzed using PopPK methods and post hoc 
estimates of antroquinonol exposure (i.e., Cmax, Ctrough, and AUCτ) will be computed for 
exploration of potential exposure-response relationships. 
Tumor biomarkers: 
Subgroup analyses will assess the predictive value of tumor biomarkers. 
11.2 
Efficacy Assessments 
11.2.1 
Tumor Measurement 
Tumor assessment will be performed during the 12 week treatment period using computed 
tomography (CT) scan or magnetic resonance imaging (MRI) according to RECIST guideline, 
version 1.1 (see Appendix 1) at the Screening Visit, Visit 4 (42), and Visit 6 (84). Tumor 
assessments will be performed every 12 weeks during the Extension Phase. The tumor 
assessment does not need to be performed at the EOS Visit if this was conducted at the 
Day 84 Visit. For patients participating in the Extension Phase, the tumor assessment does 
not need to be performed at the EOS Visit if it has been assessed within 8 weeks of the EOS 
Visit. The preferred scan is a CT of the chest, abdomen, and pelvis, performed with IV 
contrast. If patients have a contraindication to iodinated contrast, such as a documented 
allergy or impaired renal function, a non-contrast CT of the chest and MRI of the abdomen 
and pelvis is permitted (MRI preferably with gadolinium contrast, though this may be omitted 
if renal impairment is severe). Imaging evaluation at the Screening Visit must be performed 
within 14 (± 7) days of the date of first administration of study drug. 
The same method of assessment will be used at each tumor assessment visit as used at the 
baseline visit. 


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11.2.2 
Clinical Response – Solid Tumors 
Clinical response will be evaluated according to RECIST criteria25 in evaluable patients, by 
comparing the measurements and number of target lesions at baseline and during the study. 
The RECIST version 1.1 guidelines for measurable, non-measurable, target and non-target 
lesions and the objective tumor response criteria are in Appendix 1. 
11.2.3 
Tumor Biomarkers 
Formalin fixed paraffin embedded (FFPE) tumor tissue will be submitted for analysis of 
tumor biomarkers. Next-generation sequencing will be used to screen a panel of 236 genes 
commonly mutated in tumors, including KRAS, EGFR, and ALK. Patients will be stratified 
according to KRAS mutation status to test for possible differences in sensitivity/resistance to 
the study drug. In addition, selected samples may also have ALK and ROS1 status 
determined by immunohistochemistry. 
Refer to the Laboratory Manual for details of the mutation assays, and instructions for sample 
collection, handling, and shipment. 
 
 


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12 
PHARMACOKINETICS 
12.1 
Pharmacokinetic Sampling 
PK sampling will be performed on Day 0 and Day 28 in all patients enrolled in Stage 1 at the 
following time points: 
Day 0: (Approximately 5 mL per sample, 60 mL in total) 30 minutes prior to and 0.5, 1, 2, 3, 
4, 6, and 8 hours after the first dose. 
Day 28: (Approximately 5 mL per sample, 60 mL in total) immediately before and 0.5, 1, 2, 
3, 4, 6, and 8 hours after the first dose on Day 28. 
Sparse PK sampling will be performed on Days 28, 42, and 56 in all patients enrolled in 
Stage 2. At least two samples will be collected on each occasion, one of which will be a 
trough concentration (30 minutes prior to the first dose on Days 28, 42, and 56 and 
approximately 8 hours after the last dose on the prior day). At least one sample per patient 
will be timed to coincide with the peak concentration (3 hours after the first dose). The 
remainder may be taken at any time during the dosing interval. 
Each blood sample will be analyzed for antroquinonol plasma concentration to determine PK 
parameters after administration of antroquinonol using a fully validated bioanalytical method 
(a copy of the analytical method validation report and bioanalytical report will be included in 
the clinical study report). 
12.2 
Pharmacokinetic Sampling Procedures 
12.2.1 
Blood Samples 
Samples of venous blood will be obtained in 5 mL sodium heparin Vacutainer® tubes at the 
sample times listed above in Section 12.1. Immediately after collection the tube will be gently 
inverted 8 to 10 times to mix the anticoagulant with the blood sample. All samples will be 
processed and placed into a freezer within one (1) hour after collection. The plasma fraction 
will be separated by placing the collection tube into a refrigerated centrifuge (4°C) for 
10 minutes at 3000 rpm. The plasma fraction will be withdrawn by pipette and divided into 
two polypropylene freezing tubes (with each tube receiving approximately equal aliquots). 
All sample collection and freezing tubes will be clearly labeled with the patient number, the 
study period, and the collection time. Labels will be fixed to freezing tubes in a manner that 
will prevent the label from becoming detached after freezing. All plasma samples will be 
placed into a freezer at -70°C within 1 hour after collection. 
12.2.2 
Sample Storage and Shipping 
All plasma samples will be stored frozen (at -70°C) until they are shipped to the Central 
Laboratory Facility. Prior to shipping, the samples will be packed into thermal insulated 
containers and packed in sufficient dry ice to assure they remain frozen, and are protected 
from breakage during shipment. Samples will be shipped by overnight, priority courier. The 
samples will be divided into two shipments, each containing one aliquot of plasma for each 
time point. After receipt of verification that the first shipment was received by the Central 


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Laboratory Facility in good condition, the second shipment will be sent to the Central 
Laboratory Facility. 
Samples will be shipped monthly to the Central Laboratory Facility. The shipping address 
and contact information will be provided in a separate document. 
12.2.3 
Analytical Methodology 
The concentration of study drug will be determined from the plasma samples using a 
validated analytical method. Details of the method validation and sample analysis will be 
included in the final clinical study report. 


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13 
ASSESSMENT OF SAFETY 
Safety will be assessed based on AEs, clinical laboratory results (routine hematology and 
biochemistry), physical examination, vital signs, and ECG recording. 
13.1 
Height and Weight  
Height is to be measured for the patient not wearing shoes at the Screening Visit and will be 
rounded to the nearest centimeter. Weight and BMI will be measured at Screening Visit only. 
13.2 
Demographics  
Demographic data including date of birth and gender information will be obtained at 
Screening. 
13.3 
Medical History  
General medical history should be recorded at the Screening Visit. The medical history 
should include procedural and surgical history within the past year. Cancer history should be 
recorded on a life-time basis. 
13.4 
Previous and Concomitant Medications  
All previous medications taken by the patient during the 6-week period prior to study 
enrollment should be recorded at the Screening Visit. Cancer therapies should be recorded on 
a life-time basis. All concomitant medications starting from enrollment of patients should be 
recorded. 
13.5 
Physical Examination  
Patients will be examined at every visit by standard physical examination including general 
appearance, skin, eyes, ear/nose/throat, head and neck, heart, chest and lungs, abdomen, 
extremities, lymph nodes, musculoskeletal, neurological, and other body systems if 
applicable for describing the status of their health. 
13.6 
Vital Signs  
Vital signs will be measured for all patients at every visit and include blood pressure, pulse 
rate, respiratory rate, and body temperature. 
13.7 
Electrocardiograms  
Electrocardiograms will be performed at every visit, except Visit 2. The evaluation items for 
all ECGs will include heart rate, QRS complex, QT interval, QTc, and RR intervals. At 
Screening the investigator should examine the ECG for signs of cardiac disease that could 
exclude the patient from the study. An assessment of normal or abnormal will be recorded 
and if the ECG is considered abnormal, the abnormality will be documented on the eCRF. 
13.8 
Eastern Cooperative Oncology Group Performance Status  
The performance status of patients will be graded by their ECOG performance status score at 
every visit, except Visit 2. The description of ECOG performance status scale is defined as 
follows: 


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0: Normal activity. Fully active, able to carry on all pre-disease performance without 
restriction.  
1: Symptoms, but ambulatory. Restricted in physically strenuous activity, but ambulatory 
and able to carry out work of a light or sedentary nature (e.g., light housework, office 
work).  
2: In bed <50% of the time. Ambulatory and capable of all self-care, but unable to carry 
out any work activities. Up and about more than 50% of waking hours.  
3: In bed >50% of the time. Capable of only limited self-care, confined to bed or chair 
more than 50% of waking hours.  
4: 100% bedridden. Completely disabled. Cannot carry on any self-care. Totally confined 
to bed or chair.  
5: Dead.  
13.9 
Laboratory Variables  
Blood laboratory tests including red blood cells, white blood cells with differential counts, 
platelet count, hemoglobin, hematocrit, sodium, potassium, calcium, magnesium, phosphorus, 
glucose, blood urea nitrogen, creatinine, uric acid, albumin, total protein, alkaline 
phosphatase, ALT, AST, total bilirubin, gamma glutamyltransferase, and C-reactive protein 
will be taken at every visit. Urinalysis including pH, erythrocyte, leukocyte, glucose, and 
protein will be conducted at the same visits at which blood laboratory tests are performed. All 
tests will be performed at the Central Laboratory Facility. 
All Screening laboratory results must be available and reviewed before the patient receives 
the first dose of study drug at Visit 1 (Day 0). After the test results are evaluated, the 
investigators should judge whether patients are still eligible to stay in the study. Significant 
abnormal values occurring during the study will be followed until repeat test results return to 
normal, stabilize, or are no longer clinically significant. 
13.10 
Adverse Events  
An AE is any untoward medical occurrence in a patient during participation in the study, 
regardless of the relationship of the occurrence to the treatment with the study drug. An AE 
can be any unfavorable sign or symptom or diagnosed new disease or deterioration of 
existing chronic or intermittent diseases, significantly unexpected deteriorated condition of 
the study indication, which is associated with the use of the study drug. Abnormal can be 
considered as aforementioned signs and can be considered an AE. However, hospital 
admissions and/or surgical operations scheduled prior to the participation in this study for a 
pre-existing illness or disease to be performed during participation in this study are not to be 
considered an AE. The investigators are responsible for the detection, reporting, and 
documentation of AEs. 


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13.10.1 
Disease-Related Events  
A disease-related event is defined as an event that can be explained by the study indication. 
Considering the nature of the study patients to be late-stage cancer patients, the natural course 
of the disease leading to death or life-threatening conditions is considered as AEs or SAEs. 
The investigator must judge whether the event is a consequence or progression of the 
pre-existing disease(s). Disease-related events, like any other events that are life-threatening, 
or result in death, must be reported as SAEs. 
13.10.2 
Lack of Efficacy  
Lack of efficacy is not to be considered as an AE. The signs and symptoms or clinical 
sequelae resulting from lack of efficacy will be reported if they fulfill the definitions of AE or 
SAE. 
13.10.3 
Clinical Laboratory Abnormalities  
Abnormal laboratory findings and/or assessments that are judged by the investigator to be 
clinically significant will be reported as AEs or SAEs if they meet the definitions set forth. 
For the conditions that the abnormal laboratory and/or assessment findings are considered as 
the underlying disease-related, and are not unexpectedly worsened during the study, no AE or 
SAE should be reported. 
13.10.4 
Recording AEs and SAEs  
All AEs and SAEs should be documented in the source documents and the relevant eCRF and 
SAE form when applicable. The investigator may be asked to provide photocopies of the 
medical records for completing the AE or SAE report. The medical records submitted to the 
relevant parties will be concealed of the patients’ names. It is the responsibility of the 
investigator to report AEs or SAEs by diagnosis terminologies, if possible. When the 
diagnosis is possible for the reported AE or SAE, no signs and symptoms used to establish 
that particular diagnosis should be reported. The investigator will be asked to determine the 
severity and causality of each AE and SAE based on the investigator’s clinical judgment. 
Five levels of intensity and two levels of causality are used to evaluate each AE and SAE as 
shown below: 
Severity based on the National Cancer Institute (NCI) CTCAE version 4.03: 
• Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
• Grade 2: Moderate; minimal, local or non-invasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living. 
• Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
activities of daily living. 
• Grade 4: Life-threatening consequences; urgent intervention indicated. 
• Grade 5: Death related to AE. 


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*There is no direct relationship for severity and seriousness of an AE. 
Causality: 
• Possibly related: The suspected AE may follow a reasonable temporal sequence from test 
drug administration but could have been produced or mimicked by the patient’s clinical 
state or by other modes of therapy concomitantly administered to the patient. 
• Unrelated: Should be reserved for those events which occur prior to unrelated test drug 
administration (i.e., washout or single-masked placebo) or those events which cannot be 
even remotely related to study participation (e.g., injuries sustained in an automobile 
accident). 
It is important for the investigators to take information of underlying diseases, concomitant 
drugs, and temporal relationship of the onset of the event to the time of dosing the study drug, 
and re-challenging outcomes, into account when making a causal relation decision. It is the 
investigators’ responsibility to follow proactively the outcome of each AE until resolution or 
stabilization of the condition, alternative treatment for NSCLC is started, 6 months after last 
dose of study drug, or loss to follow-up, whichever occurs first. In the event of serious or 
study drug-related toxicities, the patient will be followed until resolution or stabilization. 
Safety follow-up data may be collected by telephone contact every 3 months after the EOS 
Visit. 
13.10.5 
Serious Adverse Events  
An SAE is an AE that leads to any of the following medical occurrence: 
• Results in death  
• Is life-threatening, meaning the patient is at risk of death at the time of event 
• Requires hospitalization or prolongation of existing hospitalization. Emergency room 
visits that do not result in admission to the hospital should not be considered as a SAE 
requiring hospitalization or prolongation of existing hospitalization, and such emergency 
room visits should be evaluated for one of the other serious outcomes instead 
• Results in disability/incapacity 
• Is a congenital anomaly/birth defect  
• Events requiring medical and/or surgical intervention to prevent one of the other 
outcomes listed in the definition above or, based on medical and/or scientific judgment of 
investigator, are important and should be considered serious 
Any hospitalization only for the purpose of diagnostic or study-related procedures is not to be 
considered as a serious AE. 
Any SAE, including death from any cause that occurred during the study, whether or not 
related to the study drug, must be reported to the Safety Desk immediately (within 24 hours) 
via telephone, fax, or e-mail. If initially reported via telephone or e-mail, this must be 
followed up by a written report to be submitted within 24 hours of its occurrence. 


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Serious Adverse Event Reporting  
ICON Clinical Research 
Medical & Safety Services 
United States of America - Serious Adverse Event Reporting 
Phone: +1 888 723 9952 
Fax: +1 215 616 3096 
e-mail: ICR-MA-SAE-USA@iconplc.com 
Taiwan - Serious Adverse Event Reporting 
Phone: +65 6896 0378 
Fax: +65 6565 7939 
e-mail: ICR-MA-SAE-Singapore@iconplc.com  
It is imperative to report the SAE within 24 hours of its occurrence so that reporting to the 
Regulatory Agencies can be met within the required time frame (7 or 15 calendar days). 
Because of the need to report to health authorities all SAEs in a timely manner, it is vitally 
important that an investigator report immediately any AEs that would be considered serious, 
even if the PI does not consider the AE to be clinically significant or drug-related. Should the 
PI become aware of an SAE (regardless of relationship to study drug) that occurs within 
30-days after stopping the study drug, the SAE must be reported in accordance with the 
procedures specified in this protocol. There is no time limit on the collection of SAEs that are 
considered related to study drug. All SAEs that are not resolved by the end of the study, or 
that were not resolved upon discontinuation of the patient’s participation in the study, are to 
be followed until either: the AE resolves, the AE stabilizes, the AE returns to baseline values 
(if a baseline value is available), or it is shown that the AE is not attributable to the study 
drug or study conduct. Medical and scientific judgment is to be exercised in deciding whether 
expedited reporting is appropriate in other situations, such as for important medical events 
that were not immediately life-threatening or did not result in death or hospitalization but are 
jeopardizing the patient or require intervention to prevent one of the outcomes listed above. 
13.10.6 
Pregnancy 
Patients with child-bearing potential must be confirmed as not being pregnant at Screening 
and willing to use effective methods of contraception during the study and for 3 months after 
the last dose of study drug (as defined in Section 9.3.1, Inclusion Criterion 16). Following 
administration of study drug, pregnancy cases in any female patient will be reported if known 
until the patient completes or withdraws from the study. The pregnancy will be reported 
immediately by phone and by faxing a completed Pregnancy Report to the sponsor (or 
designee) within 24 hours of knowledge of the event. The pregnancy will not be processed as 
an SAE; however the investigator will follow the patient until completion of the pregnancy 
and must assess the outcome in the shortest possible time but not more than 30 days after 
completion of the pregnancy. 


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The investigator should notify the sponsor (or designee) of the pregnancy outcome by 
submitting a follow-up Pregnancy Report. If the outcome of the pregnancy meets the criteria 
for immediate classification of an SAE (e.g., spontaneous or therapeutic abortion [any 
congenital anomaly detected in an aborted fetus is to be documented], stillbirth, neonatal 
death, or congenital anomaly), the investigator will report the event by phone and by faxing a 
completed SAE form to the sponsor (or designee) within 24 hours of knowledge of the event. 


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14 
STATISTICAL EVALUATION 
14.1 
Sample Size and Power 
The study uses a two-stage design. Thirty evaluable patients (15 in each stratum) will be 
treated initially (Stage 1), with expansion to a maximum of 60 evaluable patients (Stage 2). 
Enrollment will continue until the target number of evaluable patients has been enrolled. 
The statistical design is based on literature published by Green and Dahlberg (1992)30, von 
Mehren et. al. (2012)31 and Hoang et. al. (2013)32. It is assumed that within each of the KRAS 
tumor mutation positive and negative strata, a PFS rate at 12 weeks of 40% and 35% overall 
(unselected) population will be of interest. Further testing will not be pursued if the PFS rate 
at 12 weeks is less than 15%. 
Initially, 15 evaluable patients are to be accrued within each stratum. If two or more patients 
are alive and progression-free at Week 12 within a stratum, then an additional 15 evaluable 
patients will be accrued to that stratum for a total of 30 evaluable patients. If nine or more 
patients are alive and progression-free at Week 12 within the 30 evaluable patients in the 
stratum then antroquinonol will be considered worthy of further study in that cohort. This 
design will allow a significance level of 2.8% and a power of 90.5% within each stratum. 
In addition to within-stratum hypothesis testing, this study is also designed to investigate the 
PFS rate at 12 weeks in the overall (unselected) population. If less than three patients are 
alive and progression-free at Week 12 in the first 20 evaluable patients, and the criterion for 
continuing the individual stratum are not met, then the accrual for all strata will be 
discontinued. Otherwise, a maximum of 40 additional evaluable patients will be entered 
(depending on whether any individual stratum is closed). Fifteen or more patients alive and 
progression-free at Week 12 out of the maximum 60 evaluable patients would warrant further 
study. The overall design has a significance level of 2.8% (probability of falsely declaring the 
regimen with a 15% PFS rate at 12 weeks to warrant further study) and power 95.6% 
(probability of declaring the regimen with a 35% PFS rate at 12 weeks in the overall 
population to warrant further study). 
14.2 
Statistical Methods 
All analysis will be performed in accordance with a detailed Statistical Analysis Plan (SAP). 
14.2.1 
Analysis Populations 
The primary analysis will be performed on the evaluable population. The evaluable 
population will consist of all enrolled patients who receive at least one dose of antroquinonol 
and have a valid baseline tumor assessment. A valid baseline assessment is defined as a 
readable scan (one in which the images are of high enough quality to permit accurate 
assessment of the tumor) performed within 14 (± 7) days of the date of first administration of 
study drug. For the efficacy analysis, enrollment will continue until the target number of 
evaluable patients has been enrolled. 
The full analysis set (FAS) and PPS will be used for supportive efficacy analyses. The FAS 
will consist of patients in the evaluable population who have at least one post-baseline tumor 


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assessment. The PPS will consist of patients in the FAS who do not have major protocol 
violations. 
The PK population will consist of patients in the first stage who have an evaluable PK 
profile, defined as a profile from which at least one of the PK parameters stated as endpoints 
can be estimated, and no protocol deviations that would affect the PK of antroquinonol. 
The PopPK population will consist of patients with at least two plasma concentrations and 
sufficient and reliable dosing histories. 
The Safety population will comprise all patients who are treated with at least one dose of 
study drug. 
The PRO population will consist of all patients who have completed the QoL Questionnaire 
on Day 0 and on at least one occasion after the first administration of study drug. 
14.2.2 
Efficacy Analysis 
Except for the primary efficacy analysis, there will be no formal statistical testing. All data 
will be summarized and listed as appropriate. All efficacy endpoints will be evaluated in both 
the overall (unselected) population and within-stratum. 
The primary and secondary efficacy analyses will be based on the independent centralized 
assessment of medical images. A detailed description of the process is provided in the 
Independent Review Charter. 
14.2.2.1 
Primary Efficacy Analysis 
The primary endpoint is the PFS rate at 12 weeks, defined as the proportion of patients alive 
and progression-free at Week 12. Patients will be progression-free if they have no evidence 
of progressive disease (defined according to RECIST guideline, version 1.1) from the start of 
treatment to Week 12. An evaluable patient who died from any cause or discontinued the 
study for any reason without a post-screening or Week 12 tumor assessment will be 
considered as failing to respond to treatment. 
The primary analysis will be performed on the evaluable population as defined in 
Section 14.2.1. The FAS and PPS (as defined in Section 14.2.1) will be used for supportive 
efficacy analyses. The PFS rate together with a two-sided 95% exact confidence interval (CI) 
will be calculated for the evaluable population, FAS and PPS. 
The primary analysis will follow the two-stage procedure as specified in Section 14.1. 
14.2.2.2 
Secondary Efficacy Analysis 
The FAS and PPS will be used for the secondary efficacy analyses. The secondary efficacy 
endpoints comprise the following: ORR, DCR, DR, PFS, OS and TTP. 
The ORR is defined as the proportion of patients whose best overall response is either CR or 
PR according to RECIST version 1.1. The best overall response is the best response recorded 
during the first 12-week treatment cycle. 


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The DCR is defined as the proportion of patients with a documented CR, PR and SD during 
the first 12-week treatment cycle according to the RECIST version 1.1. For both ORR and 
DCR, 95% two-sided CIs will be presented. 
The DR is defined as the interval between the date of the first observation of tumor response 
(CR or PR) and the date of disease progression or death. The DR will be summarized using 
Kaplan-Meier methods and displayed graphically where appropriate. The DR will be 
calculated for the subgroup of patients with tumor response (CR or PR). 
If the number of patients with a documented CR or PR is small then only descriptive statistics 
or listings will be presented. 
Progression-free survival is defined as the time from the date of first administration of study 
drug to objective tumor progression by RECIST version 1.1 or death due to any cause, 
whichever occurs first. The censoring rule for PFS will be described in the SAP. 
Overall survival is defined as the time from the date of first administration of study drug to 
death from any cause. The censoring rule for OS will be described in the SAP. 
Time to progression is defined as the time from the date of first administration of study drug 
to objective tumor progression by RECIST version 1.1. The censoring rule for TTP will be 
described in the SAP. 
Objective response rate and DCR will be reported with category counts, percentage and 95% 
CIs. PFS, OS and TTP will be evaluated using Kaplan-Meier estimates and curves will be 
generated based on these estimates. 
Time-to-event endpoints will be re-analyzed when all patients have completed the Extension 
Phase. 
14.2.3 
Pharmacokinetic Analysis 
Non-compartmental PK analysis will be performed for the PK population, which will consist 
of patients in the first stage who have an evaluable PK profile, defined as a profile from 
which at least one of the PK parameters stated as endpoints can be estimated and no protocol 
deviations that would affect the PK of antroquinonol. Curves of antroquinonol concentration 
versus time in plasma will be constructed for each patient. Descriptive statistics will be 
presented for all PK parameters. 
The following PK parameters will be estimated by non-compartmental methods: 
• Cmax: peak concentration 
• Ctrough: trough plasma concentration 
• Tmax: peak time 
• AUCτ: area under the plasma concentration-time curve over the 8-hour dosing interval 
• T½: terminal half-life 
• Vz/F: apparent volume of distribution during elimination 
• CL/F: apparent oral clearance 


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• T½, eff: effective half-life 
Full details of the PK analysis will be provided in the SAP. 
If possible, PK data from all patients in the PopPK population will be analyzed using PopPK 
methods and post hoc estimates of antroquinonol exposure computed for exploration of 
potential exposure-response relationships. Full details of the PopPK analysis will be provided 
in a separate modeling and simulation analysis plan (MSAP). 
14.2.4 
Safety Analysis 
All patients who are treated with at least one dose of study drug will be evaluated for safety. 
Safety data will be summarized for the overall (unselected) population and within-stratum. 
There will be no formal statistical analysis of safety data. Demographic and Screening data 
will be listed and summarized, as appropriate. All AEs will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA), graded using the NCI CTCAE version 4.03 
and listed by patient. Treatment-emergent AEs will be summarized by treatment, severity and 
causal relationship to study drug. Any serious AEs will be listed separately. 
System organ class and preferred terms within each body system will be used for frequency 
summaries. CTC grades for clinical laboratory data will be derived, and changes in CTC 
grades will be summarized by visit. Vital signs and ECG data will be listed by patient and 
summarized, as appropriate. 
Safety data followed up during the Extension Phase will be analyzed where all patients will 
complete the Extension Phase. 
14.2.5 
Patient Reported Outcome 
PRO data will be summarized for the overall (unselected) population and within-stratum. 
The EORTC QLQ-C30 is comprised of a global health status scale, five functional scales 
(physical, role, emotional, cognitive and social) and three symptom scales (fatigue, nausea 
and vomiting, pain) and six single items (dyspnea, insomnia, appetite loss, constipation, 
Diarrhea and financial difficulties). The QLQ-LC13 includes questions assessing lung 
cancer-associated symptoms (cough, hemoptysis, dyspnea and site specific pain), 
treatment-related side effects (sore mouth, dysphagia, peripheral neuropathy and alopecia) 
and pain medication. 
Descriptive statistics will be presented for both absolute scores for EORTC QLQ-C30 and 
QLQ-LC13 and changes from baseline (Day 0) at each assessment time. Scores will be 
plotted for selected symptoms. 
14.3 
Interim Analysis  
An interim analysis for safety and efficacy will be performed when 20 patients overall and 
when 15 patients within each stratum are evaluable for the primary endpoint, PFS rate at 
12 weeks. As described in Section 14.1, if less than two patients are alive and 
progression-free within a stratum, then the accrual for that stratum will be discontinued. 
Otherwise, a maximum of 15 additional evaluable patients will be accrued to that stratum for 
a total of 30 evaluable patients. Furthermore, if less than three patients in the overall 


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(unselected) population are alive and progression-free in the first 20 evaluable patients, and 
the criterion for continuing the individual stratum are not met, then the accrual for all strata 
will be discontinued. Otherwise, a maximum of 40 additional evaluable patients will be 
entered (depending on whether any individual stratum is closed). 
14.4 
Tumor Biomarkers 
Tumor tissue blocks or slides will be obtained from archival material or from fresh biopsy 
during the Screening period to determine the KRAS tumor mutation status before enrolling 
the patient into the study. A patient may be enrolled based on KRAS test results from the 
local laboratory. Pleural fluid cytology may be used to determine KRAS mutation status if 
the cytology was pathologically reviewed and reported to contain malignant cells consistent 
with NSCLC. Patients will be stratified according to KRAS mutation status to test for 
possible differences in sensitivity/resistance to the study drug. KRAS and other tumor 
biomarkers will be used in subgroup analyses to determine the molecular signature of patients 
who could benefit from antroquinonol. To that effect, tumor tissue from patients will be used 
to evaluate arrays of genomic and proteomic markers of interest. 
Full details of this analysis will be provided in the SAP. 
14.5 
Data Monitoring Committee 
An Independent Data Monitoring Committee will act in an advisory capacity to monitor 
patient safety and efficacy data from the study. The members will be selected on the basis of 
relevant experience and understanding of clinical research and the issues specific to the 
therapeutic area, as well as previous data monitoring committee experience. 
A Data Monitoring Committee charter, which includes detailed processes, will be prepared 
before the interim analysis. 


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15 
DATA HANDLING AND RECORD KEEPING 
15.1 
Informed Consent and Institutional Review 
All patients in this research study should be completely informed about the purpose, duration 
and important procedural details of the study. Informed Consent must be obtained using a 
written form which has been approved by the appropriate Independent Ethics Committee 
(IEC) or Institutional Review Board (IRB). 
The ICF will be understood and signed by each patient prior to enrollment into the study. The 
investigator will keep the original signed copies of all consent forms in his/her files and will 
provide a duplicate copy to the patient. A copy of the letter indicating IEC or IRB approval 
must be provided to the study sponsor prior to the study initiations. 
15.2 
Confidentiality/Publication of the Study 
Any information the study sponsor shares with you regarding this study, including this 
protocol, is considered proprietary information and should be kept confidential. Each 
investigator will be required to sign the signature page which affirms he/she has 
read/understood the obligations of investigators. Once the study has begun, the investigator 
will comply with the protocol as written except in instances of medical urgency. The sponsor 
and the IEC/IRB should be notified of these cases as soon as possible. Any other changes to 
the protocol must be approved by both the sponsor and the IEC/IRB prior to commencement. 
The information provided by the study sponsor in this protocol and the associated Clinical 
Investigator's Brochure29 and the data generated by this clinical study are to be considered as 
confidential property of the study sponsor. The data and information associated with this 
study may be used by the study sponsor now and in the future for the purposes of 
presentation, publication at the discretion of the study sponsor or for submission to regulatory 
agencies. In addition, relative to the release of any proprietary information, the study sponsor 
reserves the right of prior review of any publication or presentation of data from this study. 
In signing this protocol, the investigator agrees to the release of the data from this study and 
acknowledges the above publication policy. 
15.3 
Data Collection 
The clinical investigator must maintain detailed records on all study patients. Clinical data 
will be entered on eCRFs for transmission to the sponsor. The investigator will be provided a 
copy of all completed eCRFs. 
15.4 
Drug Accountability 
Site staff will record compliance of patients with their assigned treatment regimen as 
described in Section 10.11. 
The principal investigator is to keep a current record of the inventory and dispensing of all 
test drugs. This record will be made available to the sponsor monitor for the purpose of drug 
accountability checks. 


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Any significant discrepancy and/or deficiency should be recorded, with an explanation. All 
supplies to be sent to the investigator must be accounted for and the test material must not be 
used in any unauthorized situation. 
The principal investigator, upon receipt of the clinical supplies, will conduct a drug 
inventory. The drug inventory record should be returned to the sponsor and be maintained for 
the investigator's records. 
It is the principal investigator's responsibility to return all unused supplies to the sponsor at 
the completion of the study. 
15.5 
Record Retention 
All records relating to the conduct of this study are to be retained by the investigator 
according to ICH, local regulations, or as specified in the clinical study agreement, whichever 
is longer. Prior to transfer or destruction of these records, the sponsor must be notified in 
writing and given the opportunity to further store such records. The investigator will allow 
representatives of sponsor’s monitoring members (and of the applicable regulatory 
authorities) to inspect all study records, eCRFs, and corresponding portions of the study 
patient’s office and/or hospital medical records at regular intervals across the study. These 
inspections are for the purpose of verifying the adherence to the protocol, the completeness 
and accuracy of the data being filled in the eCRF, and compliance with applicable 
regulations. 
The sponsor and the investigator agree that the study patient medical records will be 
maintained in a confidential manner. The study report will not identify any patient by name. 
These reports may be submitted to the Department of Health in the Republic of China and 
any other applicable health authorities by the sponsor. 
15.6 
Case Report Forms 
Clinical data will be entered on eCRFs for transmission to the sponsor. Data on eCRFs 
transmitted via the web-based data system must correspond to and be supported by source 
documentation maintained at the study center. All study forms and records transmitted to the 
sponsor must carry only coded identifiers such that personally identifying information is not 
transmitted. The primary method of data transmittal is via the secure, internet-based 
electronic data capture (EDC) system maintained by the sponsor (or designee). Access to the 
EDC system is available to authorized users via the study’s internet website, where an 
assigned username and password are required for access. The EDC system is in compliance 
with applicable data protection guidelines and regulations. eCRFs will be considered 
complete when all missing and/or incorrect data have been resolved. 
15.7 
Source Documents 
Source documents are considered to be all information in original records and certified copies 
of original records of clinical findings, observations, data or other activities in a clinical study 
necessary for the reconstruction and evaluation of the study. 


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16 
MONITORING 
The study will be monitored to ensure that it is conducted and documented according to the 
protocol, GCP, and all applicable regulatory requirements. On-site visits will be made at 
appropriate times during the period of the study. Monitors must have direct access to source 
documentation in order to check the consistency of the data recorded in the eCRFs. 
The PI will make available to the monitor source documents, medical records, and source 
data necessary to complete eCRFs. In addition, the PI will work closely with the monitor and, 
as needed, provide them appropriate evidence that the conduct of the study is being done in 
accordance with applicable regulations and GCP guidelines. 


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17 
QUALITY CONTROL AND QUALITY ASSURANCE 
The sponsor or designee will perform the quality assurance and quality control activities of 
this study; however, responsibility for the accuracy, completeness, and reliability of the study 
data presented to the sponsor lies with the PI generating the data. 
The sponsor will arrange audits as part of the implementation of quality assurance to ensure 
that the study is being conducted in compliance with the protocol, Standard Operating 
Procedures, GCP, and all applicable regulatory requirements. Audits will be independent of 
and separate from the routine monitoring and quality control functions. 


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18 
PROTOCOL AMENDMENT AND PROTOCOL DEVIATION 
18.1 
Protocol Amendment 
Administrative amendments to the protocol will be classed as amendment of typographical 
errors, clarifications of confusing wording, name changes and minor modifications that have 
no impact on the safety of the patient or the scientific value of the study. Administrative 
amendments will be submitted to the IRB/Research Ethics Board (REB) for information only. 
The sponsor will ensure that acknowledgement is received and filed. Otherwise, an 
amendment will be classed as a substantial amendment and will be submitted to the 
appropriate Regulatory Authorities and the IRBs/REBs for approval. 
18.2 
Protocol Deviations 
No deviations from the protocol are anticipated. However, should a protocol deviation occur, 
the sponsor (and designated Clinical Research Organization personnel, such as the Medical 
Monitor and Clinical Research Associate) must be informed as soon as possible. Protocol 
deviations and/or violations and the reasons they occurred will be included in the clinical 
study report. Reporting of protocol deviations to the IRB/REB and in accordance with 
applicable Regulatory Authority mandates is a PI responsibility. 


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19 
ETHICAL CONSIDERATIONS 
This study will be conducted in accordance with the Declaration of Helsinki (see Appendix 5) 
and its most recent amendments and/or all relevant federal regulations, as set forth in Parts 
50, 56, 312, Subpart D, of Title 21 of the Code of Federal Regulations (CFR), and in 
compliance with GCP guidelines. 
Institutional Review Boards will review and approve this protocol and informed consent. All 
patients are required to give written informed consent prior to participation in the study. This 
study will be performed in accordance with GCP by qualified PIs. The study specifically 
incorporated the following features: 
• Prospectively stated objectives and analytical plan  
• Accepted, pre-specified outcome measures for safety and efficacy 
• Investigator meeting prior to study start and a detailed protocol to promote consistency 
across sites, and  
• Compliance with GCP, with assessment via regular monitoring. 
Quality assurance procedures will be performed at study sites and during data management to 
assure that safety and efficacy data are adequate and well documented. 


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20 
FINANCING AND INSURANCE 
Financial aspects of the study are addressed in a separate clinical study agreement. The PI is 
required to have adequate current insurance to cover claims for negligence and/or 
malpractice. The sponsor will provide insurance cover for the clinical study as required by 
national regulations. 


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21 
PUBLICATION POLICY 
Both the use of data and the publication policy are detailed within the clinical study 
agreement. The PI should be aware that intellectual property rights (and related matters) 
generated by the PI and others performing the clinical study will be subject to the terms of a 
clinical study agreement that will be agreed between the Institution and the sponsor or their 
designee. With respect to such rights, the sponsor or their designee will solely own all right 
and interest in any materials, data and intellectual property rights developed by PIs and others 
performing the clinical study described in this protocol, subject to the terms of any such 
agreement. In order to facilitate such ownership, PIs will be required to assign all such 
inventions either to their Institution or directly to the sponsor or their designee, as will be set 
forth in the clinical study agreement. 
 


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22 
REFERENCE LIST 
1. Horner MJ, Ries LAG, Krapcho M, Neyman N, Aminou R, Howlader N, Altekruse 
SF, Feuer EJ, Huang L, Mariotto A, Miller BA, Lewis DR, Eisner MP, Stinchcomb 
DG, Edwards BK (eds). SEER Cancer Statistics Review, 1975-2006, National Cancer 
Institute. 
2. Taiwan Cancer Registry. Cancer Statistics Report, 2006. Bureau of Health Promotion, 
Department of Health, R.O.C. (Taiwan). 
3. Schrump, DS, Giaccone G, Kelsey CR, Marks, LB. Non-Small-Cell Lung Cancer. In: 
DeVita VT, Larence TS, Rosenberg SA, eds. Cancer. Principles and Practice of 
Oncology, 8th ed. Philadelphia, LippincottWilliams &Wilkins, 2008:896-946. 
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Society of Clinical Oncology. American Society of Clinical Oncology treatment of 
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7. Stinchcombe TE, Socinski MA. Current treatments for advanced stage non-small cell 
lung cancer. Proc Am Thorac Soc. 2009 Apr 15; 6(2):233-41. 
8. Chen CC, Shiao YJ, Lin RD, Shao YY, Lai MN, Lin CC, Ng LT, and Kuo YH. 
Neuroprotective diterpenes from the fruiting body of Antrodia camphorata. J Nat 
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9. Lee TH, Lee CK, TsouWL, Liu SY, Kuo MT, and WenWC. A new cytotoxic agent 
from solid-state fermented mycelium of Antrodia camphorata. Planta Med. 2007 Oct; 
73(13):1412-5. 
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HL. Protection of oxidative damage by aqueous extract from Antrodia camphorata 
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11. Chang JM, Lee YR, Hung LM, Liu SY, Kuo MT, WenWC, and Chen PN. An extract 
of Antrodia camphorata mycelia attenuates the progression of nephritis in systemic 
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doi:10.1093/ecam/nen057. 
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Immuno-modulatingActivity of Some Active Principles Isolated from the Fruiting 
Bodies of Antrodia camphorata. The 12th International Congress of Oriental 
Medicine 2003. 
14. Song TY, and Yen GC. Protective effects of fermented filtrate from Antrodia 
camphorata in submerged culture against CCl4-induced hepatic toxicity in rats. J 
Agric Food Chem. 2003 Mar 12; 51(6):1571-7. 
15. Chen KC, Peng CC, Peng RY, Su CH, Chiang HS, Yan JH, and Hsieh-Li HM. 
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17. Yang HL, Chen CS, Chang WH, Lu FJ, Lai YC, Chen CC, Hseu TH, Kuo CT, and 
Hseu YC. Growth inhibition and induction of apoptosis in MCF-7 breast cancer cells 
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18. Ao ZH, Xu ZH, Lu HY, Xu XY, Zhang XM, and Dou WF. Niuchangchih (Antrodia 
camphorata) and its potential in treating liver diseases. J Ethnopharmacol. 
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19. Chen YS, Pan JH, Chiang BH, Lu FJ, and Sheen LY. Ethanolic extracts of Antrodia 
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The adjuvant effects of Antrodia camphorata extracts combined with antitumor 
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(CTCAE) version 4.03. 
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26. CPMP/EWP/205/95/Rev.4. Oncology Working Party. Guideline on the Evaluation of 
Anticancer Medicinal Products in Man. 13 December 2012. 
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Drugs and Biologics. May 2007. 
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Prolongation And Proarrhythmic Potential For Non-Antiarrhythmic Drugs E14. 
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30. Green SJ and Dahlberg S (1992). Planned Versus Attained Design in Phase II Clinical 
Trials. Statistics in Medicine 11:853-862. 
31. von Mehren M, Rankin C, Goldblum JR, Demetri GD, Bramwell V, Ryan CW, and 
Borden E (2012). Phase 2 Southwest Oncology Group-Directed Intergroup Trial 
(S0505) of Sorafenib in Advanced Soft Tissue Sarcomas. Cancer 118:770-776. 
32. Hoang T, Campbell TC, Zhang C, Kim KM, Kolesar JM, Oettel KR, et al. Vorinostat 
and bortezomib as third-line therapy in patients with advanced non-small cell lung 
cancer: a Wisconsin Oncology Network Phase II study. Invest New Drugs. 2013 June; 
DOI 10.1007/s10637-013-9980-5. 
 


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23 
APPENDICES 
Appendix 1 Revised Response Evaluation Criteria in Solid Tumors Guidelines 
Version 1.1 – Adaptation from original publication with addition of 
supplementary explanations 
Summary published by the National Cancer Institute based on the following publication: Eisenhauer 
EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumors: Revised RECIST 
guideline (version 1.1). Eur J Cancer. 2009 Jan; 45(2):228-47. 
Overview of assessment process 
The tumor burden will be documented at baseline. First, reviewers will determine which 
lesions are appropriate for repeated quantitative assessment (these are called “measurable” 
lesions). From the measurable lesions, reviewers will choose a set of lesions that actually will 
be followed quantitatively throughout the study (these are called “target” lesions). As 
recommended by RECIST 1.1, the target lesions will be measured in such a way as to 
maximize the reproducibility and reliability of the measurement, and a value for the target 
tumor burden (the “sum of diameters”) will be calculated. All tumor lesions that are not 
chosen for quantitative assessment will be documented and followed qualitatively as 
“non-target” lesions. 
At each Follow-Up Visit, reviewers will assess the target lesions by making the appropriate 
measurements, calculating the sum of diameters, and comparing the sum of diameters to the 
values at baseline (to look for partial response) and to the smallest value seen until that point 
(also called the “nadir” value, to look for progression). They will also assess the non-target 
lesions qualitatively, and will search for new lesions. The information about target, non-target, 
and new lesions will be combined to produce an overall visit response for the patient. After 
all of the overall visit responses have been determined, information about the endpoints will 
be extracted from the sequence of visit responses and the dates of the visits. 
Measurability of tumor at baseline  
Measurement of lesions  
All lesion measurements should be recorded in metric notation, using calipers if clinically 
assessed. All baseline evaluations should be performed as close as possible to the treatment start 
and never more than 4 weeks before the beginning of the treatment. 
Lesions other than lymph nodes are measured in their longest diameter on CT or MRI scan (or X-
ray, in limited circumstances as described above). Measurements are typically made in the axial 
plane. Lymph nodes are normal anatomical structures which may be visible by imaging even if 
not involved by tumor. Only the short axis of these nodes will contribute to the sum of diameters, 
both at baseline and at future visits. 


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Definitions  
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-measurable as 
follows: 
Measurable tumor lesions  
Tumor lesions must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of: 
• 
10 mm by CT scan (CT scan slice thickness no greater than 5 mm). 
• 
10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable). 
• 
20 mm by chest X-ray. 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node 
must be ³ 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. Nodal size is normally reported as two dimensions in the plane in which the image 
is obtained (axial for CT, possibly coronal or sagittal for MRI). For example, an abdominal node 
which is reported as being 20 mm x 30 mm has a short axis of 20 mm and qualifies as a 
malignant, measurable node. In this example, 20 mm should be recorded as the node 
measurement. 
Non-measurable tumor lesions  
Non-measurable tumor lesions encompass small lesions (longest diameter < 10 mm or 
pathological lymph nodes with ≥ 10 to < 15 mm short axis) as well as truly non-measurable 
lesions. Lesions considered truly non-measurable include: leptomeningeal disease, ascites, 
pleural or pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin 
or lung, peritoneal spread, abdominal masses/abdominal organomegaly identified by physical 
exam that is not measurable by reproducible imaging techniques. 
Pathological nodes (those with short axis ≥10 mm but <15 mm) should be considered 
non-measurable lesions. Nodes that have a short axis <10 mm are considered 
non-pathological and should not be recorded or followed. 
Special considerations regarding lesion measurability  
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment: 
Bone lesions: 
• 
Bone scan, PET scan or plain films are not considered adequate imaging techniques to 
measure bone lesions. However, these techniques can be used to confirm the presence or 
disappearance of bone lesions. 
• 
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, 
that can be evaluated by cross sectional imaging techniques such as CT or MRI can be 
considered as measurable lesions if the soft tissue component meets the definition of 
measurability described above  
• 
Blastic bone lesions are non-measurable. 
 


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Cystic lesions: 
• 
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 patient, these are preferred for selection as 
target lesions. 
Lesions with prior local treatment: 
• 
Tumor lesions situated in a previously irradiated area, or in an area subjected to other 
loco-regional therapy, are usually not considered measurable unless there has been 
demonstrated progression in the lesion, or unless the radiation took place over 6 months 
prior to enrollment. 
Notes on measurability by method of assessment  
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging based evaluation should 
always be done rather than clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
Clinical lesions: Clinical lesions are measurable only when they are superficial and at least 
10 mm in diameter, assessed using calipers. For skin lesions, documentation by color 
photography, including a ruler or size standard, is suggested. 
Chest X-ray: Chest CT is preferred over chest X-ray, since CT is more sensitive than X-ray, 
particularly in identifying new lesions. Lesions on chest X-ray may be considered measurable 
(see definitions below) if they are clearly defined and surrounded by aerated lung. Still, CT is 
preferred over chest X-ray, even if the CT is done without contrast. 
CT, MRI: CT is the best currently available and reproducible method to measure lesions 
selected for response assessment. This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm or less. When 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). The slice thickness 
for MRI (for purposes of determining measurability) is the total distance from the top of one 
slice to the top of the next slice (including any inter-slice gap). 
If prior to enrollment it is known that a patient is not able to undergo CT scans with IV contrast 
due to allergy or renal insufficiency, the patient should receive non-contrast CT of the chest, and 
MRI of the abdomen and pelvis. If the patient develops iodinated contrast allergy during the 
study, the same approach (non-contrast CR of chest, MRI of abdomen and pelvis) should be used, 
with awareness that the change in modality may render the lesions from that point forward 
non-evaluable. 
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. 


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Tumor response evaluation  
Assessment of overall tumor burden and measurable disease  
To assess objective response or future progression, it is necessary to estimate the overall tumor 
burden at baseline and use this as a comparator for subsequent measurements. Only patients with 
measurable disease at baseline will be included in this protocol. Measurable disease is defined as 
the presence of at least one measurable lesion (as detailed above). 
Baseline documentation of ‘target’ and ‘non-target’ lesions  
Target lesions are a subset of measurable lesions. Measurable lesions are defined above. When 
more than one measurable lesion is present at baseline all lesions up to a maximum of five 
lesions total (and a maximum of two lesions per organ) representative of all involved organs 
should be identified as target lesions and will be recorded and measured at baseline. This means 
in instances where patients have only one or two organ sites involved a maximum of two (one 
site) and four lesions (two sites), respectively, will be recorded. Other lesions in that organ will 
be recorded as non-target lesions (even if size is greater than 10 mm by CT scan). 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. Paired organs (the lungs, the kidneys, etc.) should be 
considered a single organ. All lymph nodes are considered a single organ. 
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 as noted above, 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. 
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline. Measurements are not required and 
these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal progression’. 
In addition, it is possible to record multiple non-target lesions involving the same organ as a 
single item on the case report form (e.g. ‘multiple enlarged pelvic lymph nodes’ or ‘multiple liver 
metastases’). 
Response criteria  
This section provides the definitions of the criteria used to determine objective tumor 
response for target lesions. 
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 diameters of target lesions, 
taking as reference the baseline sum diameters. 
• 
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target 


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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. 
• 
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. 
Special notes on the assessment of target lesions  
Lymph nodes: Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline examination), 
even if the nodes regress to below 10 mm on study. This means that when lymph nodes are 
included as target lesions, the ‘sum’ of lesions may not be zero even if complete response criteria 
are met, since a normal lymph node is defined as having a short axis of < 10 mm. Case report 
forms or other data collection methods may therefore be designed to have target nodal lesions 
recorded in a separate section where, in order to qualify for CR, each node must achieve a short 
axis <10 mm. For PR, SD and PD, the actual short axis measurement of the nodes is to be 
included in the sum of target lesions. 
Target lesions that become ‘too small to measure’: while on study, all lesions (nodal and 
non-nodal) recorded at baseline should have their actual measurements recorded at each 
subsequent evaluation, even when very small (e.g. 2 mm). However, sometimes lesions or lymph 
nodes which are recorded as target lesions at baseline become so faint on CT scan that the 
radiologist may not feel comfortable assigning an exact measure and may report them as being 
‘too small to measure’. When this occurs it is important that a value be recorded on the case 
report form: 
• 
If it is the opinion of the radiologist that the lesion has likely disappeared, the 
measurement should be recorded as 0 mm. 
• 
If the lesion is believed to be present and is faintly seen but too small to measure, a 
default value of 5 mm should be assigned and BML (below measurable limit) should be 
ticked (Note: It is less likely that this rule will be used for lymph nodes since they usually 
have a definable size when normal and are frequently surrounded by fat such as in the 
retroperitoneum; however, if a lymph node is believed to be present and is faintly seen 
but too small to measure, a default value of 5 mm should be assigned in this circumstance 
as well and BML should also be ticked). 
This default value is derived from the 5 mm CT slice thickness (but should not be changed with 
varying CT slice thickness). The measurement of these lesions is potentially non-reproducible; 
therefore providing this default value will prevent false responses or progressions based upon 
measurement error. 
To reiterate, however, if the radiologist is able to provide an actual measure, that should be 
recorded, even if it is below 5 mm and in that case BML should not be ticked. (BML is 
equivalent to a less than sign <)  
Lesions that split or coalesce on treatment: when non-nodal lesions ‘fragment’, the longest 
diameters of the fragmented portions should be added together to calculate the target lesion sum. 
Similarly, as lesions coalesce, a plane between them may be maintained that would aid in 
obtaining maximal diameter measurements of each individual lesion. If the lesions have truly 
coalesced such that they are no longer separable, the vector of the longest diameter in this 
instance should be the maximal longest diameter for the ‘coalesced lesion’. 
 


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Evaluation of non-target lesions  
This section provides the definitions of the criteria used to determine the tumor response for the 
group of non-target lesions. While some non-target lesions may actually be measurable, they 
need not be measured and instead should be assessed only qualitatively at the time points 
specified in the protocol. 
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (<10 mm short axis). 
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): Unequivocal progression of non-target lesions, evaluated as a 
whole, such that it is clear that the disease is progressing regardless of the status of the target 
lesions. 
Special notes on assessment of progression of non-target disease  
The concept of progression of non-target disease requires additional explanation as follows: 
When the patient also has measurable disease: in this setting, to achieve ‘unequivocal 
progression’ on the basis of the non-target disease, there must be an overall level of substantial 
worsening in non-target disease in a magnitude that, even in presence of SD or PR in target 
disease, the overall tumor burden has increased sufficiently to merit discontinuation of therapy. A 
modest ‘increase’ in the size of one or more non-target lesions is usually not sufficient to qualify 
for unequivocal progression status. The designation of overall progression solely on the basis of 
change in non-target disease in the face of SD or PR of target disease will therefore be extremely 
rare. 
When the patient has only non-measurable disease: this circumstance arises in some Phase III 
studies when it is not a criterion of study entry to have measurable disease. The same general 
concepts apply here as noted above, however, in this instance there is no measurable disease 
assessment to factor into the interpretation of an increase in non-measurable disease burden. 
Because worsening in non-target disease cannot be easily quantified (by definition: if all lesions 
are truly non-measurable) a useful test that can be applied when assessing patients for 
unequivocal progression is to consider if the increase in overall disease burden based on the 
change in non-measurable disease is comparable in magnitude to the increase that would be 
required to declare PD for measurable disease: i.e. an increase in tumor burden representing an 
additional 73% increase in ‘volume’ (which is equivalent to a 20% increase diameter in a 
measurable lesion). Examples include an increase in a pleural effusion from ‘trace’ to ‘large’, an 
increase in lymphangitic disease from localized to widespread, or sufficient to require a change in 
therapy. If ‘unequivocal progression’ is seen, the patient should be considered to have had overall 
PD at that point. While it would be ideal to have objective criteria to apply to non-measurable 
disease, the very nature of that disease makes it impossible to do so; therefore the increase must 
be substantial. 


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New lesions  
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important. There are no specific criteria for the 
identification of new radiographic lesions; however, the finding of a new lesion should be 
unequivocal: i.e. not attributable to differences in scanning technique, change in imaging 
modality or findings thought to represent something other than tumor (for example, some 
‘new’ bone lesions may be simply healing or flare of pre-existing lesions). 
This is particularly important when the patient’s baseline lesions show partial or complete 
response. For example, necrosis of a liver lesion may be reported on a CT scan report as a 
‘new’ cystic lesion, which it is not. 
A lesion identified on a follow-up study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression. An example of this is 
the patient who has visceral disease at baseline and while on study has a brain CT or MRI 
ordered which reveals metastases. The patient’s brain metastases are considered to be evidence 
of PD even if he/she did not have brain imaging at baseline. 
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm 
there is definitely a new lesion, then progression should be declared using the date of the 
initial scan. 
(18)F-Fluorodeoxyglucose Positron Emission Tomography (FDG-PET)  
FDG-PET scanning may complement CT scanning in assessment of progression (particularly 
possible ‘new’ disease). New lesions on the basis of FDG-PET imaging can be identified 
according to the following algorithm: 
• 
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based 
on a new lesion. 
• 
No FDG-PET at baseline and a positive FDG-PET at follow-up: 
 
If the positive FDG-PET at follow-up corresponds to a new site of disease 
confirmed by CT, this is PD. 
 
If the positive FDG-PET at follow-up is not confirmed as a new site of 
disease on CT (existing disease or uncertain whether disease is present in the 
location where the PET is positive), additional follow-up CT scans are needed 
to determine if there is truly progression occurring at that site (if so, the date 
of PD will be the date of the initial abnormal FDG-PET scan). 
 
If the positive FDG-PET at follow-up corresponds to a pre-existing site of 
disease on CT that is not progressing on the basis of the anatomic images, this 
is not PD. 
 
Missing assessments and not-evaluable designation  
When no imaging/measurement is done at all at a particular time point, the patient is not 
evaluable at that time point. If only a subset of lesion measurements are made at an assessment, 
usually the case is also considered not evaluable at that time point, unless a convincing 
argument can be made that the contribution of the individual missing lesion(s) would not 
change the assigned time point response. This would be most likely to happen in the case of 
PD. 


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For example, if a patient had a baseline sum of 50 mm with three measured lesions and at 
follow-up only two lesions were assessed, but those gave a sum of 80 mm, the patient will have 
achieved PD status, regardless of the contribution of the missing lesion. If one or more target 
lesions were not assessed either because the scan was not done, or could not be assessed because 
of poor image quality or obstructed view, the Response for Target Lesions should be “Unable to 
Assess” since the patient is not evaluable. Similarly, if one or more non-target lesions are 
indicated as ‘not assessed’, the response for non-target lesions should be “Unable to Assess” 
(except where there is clear progression). Overall response would be “Unable to Assess” if either 
the target response or the non-target response is “Unable to Assess” (except where this is clear 
evidence of progression) as this equates with the case being not evaluable at that time point. 
Time point response  
It is assumed that at each protocol specified time point, a response assessment occurs. Table 1 
below provides a summary of the overall response status calculation at each time point for 
patients who have measurable disease at baseline. 
When patients have non-measurable (therefore non-target) disease only, Table 2 is to be 
used.  
Table 1 
Time point response: patients with target (+/-non-target) disease 
Target lesions 
Non-target lesions 
New lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No  
PR 
SD 
Non-PD or not all evaluated 
No  
SD 
Not all Evaluated 
Non-PD  
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = complete response, PR = partial response, SD = stable disease, 
PD = progressive disease, and NE = inevaluable.  
 
Table 2 
Time point response: patients with non-target disease only 
Non-target lesions 
New lesions 
Overall response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PDa 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or No  
PD 
Any 
Yes 
PD 
CR=complete response, PD=progressive disease, and NE=inevaluable. 
a ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as endpoint for assessment of efficacy I some trails so to assign this category 
when no lesions can be measured is not advised. 


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Evaluation of best overall response  
The best overall response is the best response recorded from the start of the study drug until the 
end of treatment. Post-treatment assessments will not be considered in determination of best 
overall response. No new therapies are permitted by the protocol. If any other therapy is instituted 
during the study, the patient will be censored from the BOR assessment. Given the use of PFS as 
the primary efficacy endpoint, and the short timeframe of this study, confirmation of PR and CR 
is not required in this study. 
The best overall response will be determined by statistical programming once all the data for 
the patient is known. 
Special notes on response assessment  
When nodal disease is included in the sum of target lesions and the nodes decrease to ‘normal’ 
size (< 10 mm), they may still have a measurement reported on scans. This measurement should 
be recorded even though the nodes are normal in order not to overstate progression should it be 
based on increase in size of the nodes. As noted earlier, this means that patients with CR may not 
have a total sum of ‘zero’ on the case report form (eCRF). In studies where confirmation of 
response is required, repeated ‘NE’ time point assessments may complicate best response 
determination. The analysis plan for the study must address how missing data/assessments will be 
addressed in determination of response and progression. For example, in most studies it is 
reasonable to consider a patient with time point responses of PR-NE-PR as a confirmed response. 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
‘symptomatic deterioration’. Every effort should be made to document objective progression 
even after discontinuation of treatment. Symptomatic deterioration is not a descriptor of an 
objective response: it is a reason for stopping study therapy. The objective response status of 
such patients is to be determined by evaluation of target and non-target disease as shown in 
Table 1 and Table 2. 
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends upon this determination, it is recommended 
that the residual lesion be investigated (fine needle aspirate/biopsy) before assigning a status of 
complete response. 
For equivocal findings of progression (e.g. very small and uncertain new lesions; cystic changes 
or necrosis in existing lesions), treatment may continue until the next scheduled assessment. If 
at the next scheduled assessment, progression is confirmed, the date of progression should be 
the earlier date when progression was suspected. 


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Appendix 2 
Eastern Co-Operative Oncology Group Evaluation 
 
Activity Performance Description 
 
Score 
 
Fully active, able to carry on all pre-disease performance without restriction 
0 
Restricted in physically strenuous activity but ambulatory and able to carry 
out work of a light or sedentary nature, e.g., light house work, office work 
1 
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours  
2 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours 
3 
Completely disabled. Cannot carry on any self-care. Totally confined to bed 
or chair 
4 
Dead 
5 
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity And 
Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982. 
 


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Appendix 3 European Organisation for Research and Treatment of Cancer Quality of 
Life Questionnaire C30 and Lung Cancer Module (LC13) 
 
 
 
 


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Appendix 4 Reference List of Known Inducers, Inhibitors and Substrates of Selected 
Cytochrome P450 Enzymes 
Inhibitors  
2C8 
2C19 
2E1 
3A4,5,7 
Strong 
fluoxetine 
disulfiram  
HIV Antivirals:  
gemfibrozil 
fluvoxamine  
 
Strong  
 
ketoconazole  
 
indinavir  
 
lansoprazole  
 
nelfinavir  
 
omeprazole  
 
ritonavir  
 
ticlopidine2  
 
 
 
 
 
clarithromycin  
 
 
 
itraconazole  
 
 
 
ketoconazole  
 
 
 
nefazodone  
 
 
 
 
 
 
 
Moderate  
 
 
 
erythromycin  
 
 
 
grapefruit juice  
 
 
 
verapamil2  
 
 
 
diltiazem  
 
 
 
 
 
 
 
Weak  
 
 
 
cimetidine  
 
 
 
 
 
 
 
Others  
 
 
 
amiodarone  
 
 
 
NOT azithromycin  
 
 
 
fluvoxamine  
 
 
 
mibefradil  
 
 
 
troleandomycin  
A Strong inhibitor is one that causes a > 5-fold increase in the plasma AUC values 
or more than 80% decrease in clearance.  
A Moderate inhibitor is one that causes a > 2-fold increase in the plasma AUC 
values or 50-80% decrease in clearance.  
A Weak inhibitor is one that causes a > 1.25-fold but < 2-fold increase in the 
plasma AUC values or 20-50% decrease in clearance. 
Inducers  
2C8 
2C19 
2E1 
3A4,5,7 
 
 
ethanol  
carbamazepine  
 
 
isoniazid  
phenobarbital2  
 
 
 
phenytoin2  
 
 
 
pioglitazone   
 
 
 
rifabutin  
 
 
 
rifampin1  
 
 
 
St. John's wort  
 
 
 
troglitazone1  
Source: http://www.medicine.iupui.edu/clinpharm/ddis/ClinicalTable.asp 
 


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Sensitive in vivo CYP substrates and CYP substrates with narrow therapeutic range 
 
List (1) of Sensitive In Vivo CYP Substrates and CYP Substrates with Narrow 
Therapeutic Range  
CYP Enzymes Sensitive substrates (2) 
Substrates with 
narrow therapeutic 
range (3) 
CYP1A2 
Alosetron, caffeine, 
duloxetine, melatonin, ramelteon, 
tacrine, tizanidine 
Theophylline, tizanidine 
CYP2B6 (4) 
Bupropion, efavirenz 
CYP2C8 
Repaglinide (5) 
Paclitaxel 
CYP2C9 
Celecoxib 
Warfarin, phenytoin 
CYP2C19 
Lansoprazole, omeprazole, S-mephenytoin 
S-mephenytoin 
CYP3A (6) 
Alfentanil, aprepitant, budesonide, buspirone, 
conivaptan, darifenacin, darunavir, dasatinib, 
dronedarone, eletriptan, eplerenone, everolimus, 
felodipine, indinavir, fluticasone, lopinavir, 
lovastatin, lurasidone, maraviroc, midazolam, 
nisoldipine, quetiapine, saquinavir, sildenafil, 
simvastatin, sirolimus, tolvaptan, tipranavir, 
triazolam, vardenafil 
Alfentanil, astemizole, (7) 
cisapride, (7) 
cyclosporine, 
dihydroergotamine, 
ergotamine, fentanyl, 
pimozide, quinidine, 
sirolimus, tacrolimus,  
terfenadine (7) 
CYP2D6 
Atomoxetine, desipramine,  
dextromethorphan, metoprolol, 
nebivolol, perphenazine, tolterodine, 
venlafaxine 
Thioridazine 
Source: http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/ 
DrugInteractionsLabeling/ucm093664.htm. 
(1) Note that this is not an exhaustive list. For an updated list, see the following link: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/ 
DrugInteractionsLabeling/ucm080499.htm.  
(2) Sensitive CYP substrates refers to drugs whose plasma AUC values have been shown to 
increase 5-fold or higher when co-administered with a known CYP inhibitor. 
(3) CYP substrates with narrow therapeutic range refers to drugs whose exposure-response 
relationship indicates that small increases in their exposure levels by the concomitant use of 
CYP inhibitors may lead to serious safety concerns (e.g., Torsades de Pointes). 
(4) The AUC of these substrates were not increased by 5-fold or more with a CYP2B6 
inhibitor, but they represent the most sensitive substrates studied with available inhibitors 
evaluated to date. 
(5) Repaglinide is also a substrate for OATP1B1, and it is only suitable as a CYP2C8 
substrate if the inhibition of OATP1B1 by the investigational drug has been ruled out.  
(6) Because a number of CYP3A substrates (e.g., darunavir, maraviroc) are also substrates of 
P-gp, the observed increase in exposure could be due to inhibition of both CYP3A and P-gp. 
(7) Withdrawn from the United States market because of safety reasons. 
 


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Appendix 5 
Declaration of Helsinki  
World Medical Association Declaration of Helsinki: 
Recommendations Guiding Physicians in Biomedical Research 
Involving Human Patients  
Adopted by the 18th World Medical Association (WMA) General Assembly, Helsinki, Finland, 
1964 and amended by the WMA General Assembly, Tokyo, Japan in 1975, Venice, Italy in 1983, 
Hong Kongin 1989, Somerset West, Republic of South Africa, 1996, Edinburgh, Scotland in 
2000, added with Note of Clarification on paragraph 29 by the WMA General Assembly, 
Washington in 2002, added with Note of Clarification on paragraph 30 by the WMA General 
Assembly, Tokyo 2004, and amended by the WMA General Assembly, Seoul, 2008. 
A. Introduction  
1. The World Medical Association (WMA) has developed the Declaration of Helsinki as a 
statement of ethical principles for medical research involving human subjects, including 
research on identifiable human material and data. The Declaration is intended to be read 
as a whole and each of its constituent paragraphs should not be applied without 
consideration of all other relevant paragraphs. 
2. Although the Declaration is addressed primarily to physicians, the WMA encourages 
other participants in medical research involving human patients to adopt these principles. 
3. It is the duty of the physician to promote and safeguard the health of subjects, including 
those who are involved in medical research. The physician's knowledge and conscience 
are dedicated to the fulfillment of this duty. 
4. The Declaration of Geneva of the WMA binds the physician with the words, “The health 
of my patient will be my first consideration,” and the International Code of Medical 
Ethics declares that, “A physician shall act in the subject's best interest when providing 
medical care.”  
5. Medicalprogressisbasedonresearchthatultimatelymustincludestudiesinvolving human 
patients. Populations that are underrepresented in medical research should be provided 
appropriate access to participation in research. 
6. In medical research involving human subjects, the well-being of the individual research 
subject must take precedence over all other interests. 
7. The primary purpose of medical research involving human subjects is to understand the 
causes, development and effects of diseases and improve preventive, diagnostic and 
therapeutic interventions (methods, procedures and treatments). Even the best current 
interventions must be evaluated continually through research for their safety, 
effectiveness, efficiency, accessibility and quality. 
8. In medical practice and in medical research, most interventions involve risks and burdens. 
9. Medical research is subject to ethical standards that promote respect for all human 
subjects and protect their health and rights. Some research populations are particularly 
vulnerable and need special protection. These include those who cannot give or refuse 
consent for themselves and those who may be vulnerable to coercion or undue influence. 
10. Physicians should consider the ethical, legal and regulatory norms and standards for 


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research involving human subjects in their own countries as well as applicable 
international norms and standards. No national or international ethical, legal or regulatory 
requirement should reduce or eliminate any of the protections for research subjects set 
forth in this Declaration. 
 
B. PRINCIPLES FOR ALL MEDICAL RESEARCH  
11. It is the duty of physicians who participate in medical research to protect the life, health, 
dignity, integrity, right to self-determination, privacy, and confidentiality of personal 
information of research subjects. 
12. Medical research involving human subjects must conform to generally accepted scientific 
principles, be based on a thorough knowledge of the scientific literature, other relevant 
sources of information, and adequate laboratory and, as appropriate, animal 
experimentation. The welfare of animals used for research must be respected. 
13. Appropriate caution must be exercised in the conduct of medical research that may harm 
the environment. 
14. The design and performance of each research study involving human subjects must be 
clearly described in a research protocol. The protocol should contain a statement of the 
ethical considerations involved and should indicate how the principles in this Declaration 
have been addressed. The protocol should include information regarding funding, 
sponsors, institutional affiliations, and other potential conflicts of interest, incentives for 
subjects and provisions for treating and/or compensating subjects who are harmed as a 
consequence of participation in the research study. The protocol should describe 
arrangements for post-study access by study subjects to interventions identified as 
beneficial in the study or access to other appropriate care or benefits. 
15. The research protocol must be submitted for consideration, comment, guidance and 
approval to a research ethics committee before the study begins. This committee must be 
independent of the researcher, the sponsor and any other undue influence. It must take 
into consideration the laws and regulations of the country or countries in which the 
research is to be performed as well as applicable international norms and standards but 
these must not be allowed to reduce or eliminate any of the protections for research 
subjects set forth in this Declaration. The committee must have the right to monitor 
ongoing studies. 
 
The researcher must provide monitoring information to the committee, especially 
information about any serious adverse events. No change to the protocol may be made 
without consideration and approval by the committee. 
16. Medical research involving human subjects must be conducted only by individuals with 
the appropriate scientific training and qualifications. Research on patients or healthy 
volunteers requires the supervision of a competent and appropriately qualified physician 
or other health care professional. The responsibility for the protection of research subjects 
must always rest with the physician or other healthcare professional and never the 
research subjects, even though they have given consent. 
17. Medical research involving a disadvantaged or vulnerable population or community is 
only justified if the research is responsive to the health needs and priorities of this 
population or community and if there is a reasonable likelihood that this population or 
community stands to benefit from the results of the research. 
18. Every medical research study involving human subjects must be preceded by careful 
assessment of predictable risks and burdens to the individuals and communities involved 
in the research in comparison with foreseeable benefits to them and to other individuals or 
communities affected by the condition under investigation. 
 


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19. Every clinical trial must be registered in a publicly accessible database before recruitment 
of the first subject. 
20. Physicians may not participate in a research study involving human subjects unless they 
are confident that the risks involved have been adequately assessed and can be 
satisfactorily managed. Physicians must immediately stop a study when the risks are 
found to outweigh the potential benefits or when there is conclusive proof of positive and 
beneficial results. 
21. Medical research involving human subjects may only be conducted if the importance of 
the objective outweighs the inherent risks and burdens to the research subjects. 
22. Participation by competent individuals as subjects in medical research must be voluntary. 
Although it may be appropriate to consult family members or community leaders, no 
competent individual may be enrolled in a research study unless he or she freely agrees. 
23. Every precaution must be taken to protect the privacy of research subjects and the 
confidentiality of their personal information and to minimize the impact of the study on 
their physical, mental and social integrity. 
24. In medical research involving competent human subjects, each potential subject must be 
adequately informed of the aims, methods, sources of funding, any possible conflicts of 
interest, institutional affiliations of the researcher, the anticipated benefits and potential 
risks of the study and the discomfort it may entail, and any other relevant aspects of the 
study. The potential subject must be informed of the right to refuse to participate in the 
study or to withdraw consent to participate at any time without reprisal. Special attention 
should be given to the specific information needs of individual potential subjects as well 
as to the methods used to deliver the information. After ensuring that the potential subject 
has understood the information, the physician or another appropriately qualified 
individual must then seek the potential subject’s freely-given informed consent, 
preferably in writing. If the consent cannot be expressed in writing, the non-written 
consent must be formally documented and witnessed. 
25. For medical research using identifiable human material or data, physicians must normally 
seek consent for the collection, analysis, storage and/or reuse. There may be situations 
where consent would be impossible or impractical to obtain for such research or would 
pose a threat to the validity of the research. In such situations the research may be done 
only after consideration and approval of a research ethics committee. 
26. When seeking informed consent for participation in a research study the physician should 
be particularly cautious if the potential subject is in a dependent relationship with the 
physician or may consent under duress. In such situations the informed consent should be 
sought by an appropriately qualified individual who is completely independent of this 
relationship. 
27. For a potential research subject who is incompetent, the physician must seek informed 
consent from the legally authorized representative. These individuals must not be 
included in a research study that has no likelihood of benefit for them unless it is intended 
to promote the health of the population represented by the potential subject, the research 
cannot instead be performed with competent persons, and the research entails only 
minimal risk and minimal burden. 
28. When a potential research subject who is deemed incompetent is able to give assent to 
decisions about participation in research, the physician must seek that assent in addition 
to the consent of the legally authorized representative. The potential subject’s dissent 
should be respected. 
29. Research involving subjects who are physically or mentally incapable of giving consent, 
for example, unconscious patients, may be done only if the physical or mental condition 
that prevents giving informed consent is a necessary characteristic of the research 
population. In such circumstances the physician should seek informed consent from the 
legally authorized representative. If no such representative is available and if the research 


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cannot be delayed, the study may proceed without informed consent provided that the 
specific reasons for involving subjects with a condition that renders them unable to give 
informed consent have been stated in the research protocol and the study has been 
approved by a research ethics committee. Consent to remain in the research should be 
obtained as soon as possible from the subject or a legally authorized representative. 
30. Authors, editors and publishers all have ethical obligations with regard to the publication 
of the results of research. Authors have a duty to make publicly available the results of 
their research on human subjects and are accountable for the completeness and accuracy 
of their reports. They should adhere to accepted guidelines for ethical reporting. Negative 
and inconclusive as well as positive results should be published or otherwise made 
publicly available. Sources of funding, institutional affiliations and conflicts of interest 
should be declared in the publication. Reports of research not in accordance with the 
principles of this Declaration should not be accepted for publication. 
 
C. ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH MEDICAL 
CARE  
31. The physician may combine medical research with medical care only to the extent that the 
research is justified by its potential preventive, diagnostic or therapeutic value and if the 
physician has good reason to believe that participation in the research study will not 
adversely affect the health of the patients who serve as research subjects. 
32. The benefits, risks, burdens and effectiveness of a new intervention must be tested against 
those of the best current proven intervention, except in the following circumstances: 
• 
The use of placebo, or no treatment, is acceptable in studies where no current proven 
intervention exists; or  
• 
Where for compelling and scientifically sound methodological reasons the use of placebo 
is necessary to determine the efficacy or safety of an intervention and the patients who 
receive placebo or no treatment will not be subject to any risk of serious or irreversible 
harm. Extreme care must be taken to avoid abuse of this option. 
33. At the conclusion of the study, patients entered into the study are entitled to be informed 
about the outcome of the study and to share any benefits that result from it, for example, 
access to interventions identified as beneficial in the study or to other appropriate care or 
benefits. 
34. The physician must fully inform the patient which aspects of the care are related to the 
research. The refusal of a patient to participate in a study or the patient’s decision to 
withdraw from the study must never interfere with the patient-physician relationship. 
35. In the treatment of a patient, where proven interventions do not exist or have been 
ineffective, the physician, after seeking expert advice, with informed consent from the 
patient or a legally authorized representative, may use an unproven intervention if in the 
physician's judgment it offers hope of saving life, re-establishing health or alleviating 
suffering. Where possible, this intervention should be made the object of research, 
designed to evaluate its safety and efficacy. In all cases, new information should be 
recorded and, where appropriate, made publicly available. 

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN 
 
 
A Single-Arm, Open-Label, Phase II Trial Evaluating the Efficacy, Safety and 
Pharmacokinetics of Antroquinonol in Patients with Stage IV (including Pleural 
Effusion) Non-Squamous Non-Small Cell Lung Cancer (NSCLC) who have Failed 
Two Lines of Anti-Cancer Therapy 
 
Version: Final 1.0 
Date: 08 Aug 2014 
For 
Protocol No : GHNSCLC-2-001 Final 3.0 
Date : 04 March 2014 
Submitted to : 
Golden Biotechnology Corporation 
15F, No. 27-6, Sec. 2, Zhongzheng E. Rd., 
Tamsui Dist., New Taipei city 251, Taiwan 
 
 
Prepared by : 
ICON Clinical Research Ltd. 
 
Confidentiality Statement 
The confidential information in this document is provided to you as an Investigator, 
potential Investigator or consultant for review by you, your staff and applicable 
Independent Ethics Committee and/or Institutional Review Board (IEC/IRB).  It is 
understood that the information will not be disclosed to others without written 
authorization from Golden Biotechnology Corp. except to the extent necessary to obtain 
informed consent from those persons to whom the drug may be administered. 
 
 
 






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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ............................................................................................... 6 
1. 
INTRODUCTION ......................................................................................................... 9 
2. 
STUDY OBJECTIVES ................................................................................................ 10 
2.1 
Objectives ........................................................................................................ 10 
2.1.1 Primary Objective .................................................................................... 10 
2.1.2 Secondary Objective ................................................................................ 10 
2.1.3 Exploratory Objective .............................................................................. 10 
3. 
STUDY DESIGN ........................................................................................................ 11 
3.1 
Study Design and Population ............................................................................ 11 
3.2 
Study Treatments and Assessments .................................................................. 11 
4. 
ANALYSIS VARIABLES ........................................................................................... 15 
5. 
SAMPLE SIZE AND POWER .................................................................................... 17 
6. 
METHODS OF ANALYSIS AND PRESENTATION ................................................. 18 
6.1 
General Principles and Considerations .............................................................. 18 
6.2 
Presentation of Output ...................................................................................... 18 
6.2.1 Definition of Baseline and Visit Windows ............................................... 18 
6.2.2 Missing data or partial date handling........................................................ 20 
6.2.3 Version Numbers ..................................................................................... 21 
6.3 
Analysis Sets .................................................................................................... 21 
6.3.1 Safety Population ..................................................................................... 21 
6.3.2 Evaluable Population ............................................................................... 21 
6.3.3 Full Analysis Set (FAS) ........................................................................... 21 
6.3.4 Per-Protocol Set (PPS) ............................................................................. 22 
6.3.5 PK Population ......................................................................................... 22 
6.3.6 Population-Based PK (PopPK) Population ............................................... 22 
6.3.7 Patient Reported Outcome (PRO) Population ........................................... 22 
6.4 
Major Protocol Violations/Deviations ............................................................... 22 
6.5 
Disposition ....................................................................................................... 22 
6.6 
Demographics and Baseline Characteristics ...................................................... 23 
6.7 
Prior and Concomitant medication .................................................................... 23 
6.8 
Treatment Compliance and exposure ................................................................ 23 
6.9 
Efficacy Analysis ............................................................................................. 24 
6.9.1 Primary Endpoint ..................................................................................... 24 
6.9.2 Secondary Endpoint(s) ............................................................................. 25 
6.10 
PK Analysis ..................................................................................................... 28 
6.10.1 Noncompartmental Pharmacokinetic Analysis (NCA) ........................... 28 


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6.10.2 Treatment of Outliers ............................................................................ 29 
6.10.3 Non-Quantifiable Concentrations .......................................................... 29 
6.10.4 PopPK Analysis .................................................................................... 30 
6.10.5 Reporting of Concentrations and PK Parameters ................................... 30 
6.11 
Patient Reported Outcome ................................................................................ 30 
6.12 
Safety Analysis ................................................................................................ 31 
6.12.1 Adverse Events ..................................................................................... 31 
6.12.2 Deaths .................................................................................................. 32 
6.12.3 Clinical Laboratory Evaluations ............................................................ 32 
6.12.4 Vital Signs ............................................................................................ 32 
6.12.5 12-Lead ECGs ...................................................................................... 32 
6.12.6 Physical Examinations .......................................................................... 32 
6.13 
Subgroup Analysis ........................................................................................... 33 
6.14 
Interim Analysis and Data and Safety Monitoring Board (DSMB) .................... 33 
6.15 
Analysis for Extension Phase ........................................................................... 33 
6.16 
Changes to Planned Analyses ........................................................................... 34 
7. 
REFERENCEs ............................................................................................................. 35 
APPENDIX I: DSMB TFLS SPECIFICATIONS ................................................................ 36 
APPENDIX II: INDEPENDENT REVIEW CHARTER ..................................................... 38 
APPENDIX III: QOL SCORING CONVENTIONS............................................................ 39 
 
 


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LIST OF ABBREVIATIONS 
AE 
Adverse Event 
AUC0-∞ 
Area under the concentration-time curve from time zero 
extrapolated to infinity 
AUC0-t 
Area under the concentration-time curve from time zero (pre-dose) 
to time of last observed concentration 
AUCextr 
Proportion of area under the concentration-time curve from time 
zero extrapolated to infinity due to extrapolation 
AUCτ 
Area under the plasma concentration-time curve over the 8-hour 
dosing interval 
BMI 
Body mass index 
CL/F 
Apparent oral clearance 
Clast 
Last temporal predicted plasma concentration 
Cmax 
Peak concentration 
CR 
Complete response 
CSR 
Clinical study report 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
Ctrough 
Trough plasma concentration 
CV 
Coefficient of variation 
DCR 
Disease control rate 
DLT 
Dose limiting toxicity 
DOR 
Duration of response 
DSMB 
Data and Safety Monitoring Board 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EGFR 
Epidermal growth factor receptor 
EORTC 
European Organization for Research and Treatment of Cancer 
EOS 
End of Study 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 


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GCP 
Good Clinical Practice 
HR 
Heart rate 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IMI 
ICON Medical Imaging 
IRB 
Institutional Review Board 
LLOQ 
Lower limit of quantitation 
λz 
Terminal phase elimination rate constant 
MedDRA 
Medical Dictionary for Regulatory Activities 
MTD 
Maximum tolerated dose 
MRI 
Magnetic resonance imaging 
MSAP 
Modeling and simulation analysis plan 
NCA 
Noncompartmental pharmacokinetic analysis 
NR 
No result 
NSCLC 
Non-small cell lung cancer 
ORR 
Objective response rate 
OS 
Overall survival 
PD 
Progressive disease 
PFS 
Progression-free survival 
PK 
Pharmacokinetic(s) 
PopPK 
Population-based pharmacokinetic(s) 
PPS 
Per-protocol set 
PR 
Partial response 
PRO 
Patient Reported Outcome 
QLQ 
Quality of Life Questionnaires 
QoL 
Quality of Life 
QTc 
Corrected QT 
RAUC 
Accumulation ratio for the area under the plasma concentration-
time curve over the 8-hour dosing interval 
RECIST 
Response Evaluation Criteria in Solid Tumors 


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Rsq 
Adjusted coefficient of determination 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SCLC 
Small cell lung cancer 
SD 
Stable disease 
STD 
Standard Deviation 
TEAE 
Treatment-emergent adverse event 
τ 
Dosing interval duration 
T½ 
Terminal half-life 
T½,eff 
Effective half-life 
TFLs 
Tables, Figures, and Listings 
Tmax 
Peak time 
t.i.d. 
Three-times-a-day 
TTP 
Time to progression 
Vz/F 
Apparent volume of distribution during elimination 
 
 


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1. INTRODUCTION 
The purpose of this document is to describe the statistical methods, data derivations and data 
summaries to be employed in a single-arm, open-label, Phase II trial evaluating the efficacy, 
safety and pharmacokinetics of antroquinonol in patients with stage IV (including pleural 
effusion) non-squamous non-small cell lung cancer (NSCLC) who have failed two lines of 
anti-cancer therapy. 
The preparation of this Statistical Analysis Plan (SAP) has been based on International 
Conference on Harmonisation (ICH) E31 and E92 Guidelines and in reference to Clinical 
Study Protocol v3, draft dated 26 February 2014. 
 
In accordance with ICH E9, prior to locking the database and before executing the statistical 
analysis a Data Review Meeting will be held. The purpose of this meeting will be to  
 
1. Determine the evaluability of patients and finalize the analysis populations as defined 
in the protocol and/or the statistical analysis plan (SAP) 
2. Assess protocol deviations 
3. Review completeness and reliability of the data 
 
 


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2. STUDY OBJECTIVES 
2.1 Objectives 
2.1.1 Primary Objective 
To evaluate the activity of antroquinonol in unselected, KRAS-positive, and KRAS-negative 
patients with stage IV (including pleural effusion) non-squamous NSCLC who have failed 
two lines of anti-cancer therapy. 
 
2.1.2 Secondary Objective 
To assess the safety and tolerability and pharmacokinetics (PK) of antroquinonol in patients 
with stage IV (including pleural effusion) non-squamous NSCLC who have failed two lines 
of anti-cancer therapy. 
 
2.1.3 Exploratory Objective 
To explore potential relationships between antroquinonol exposure and safety and efficacy 
endpoints. 


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3. STUDY DESIGN 
3.1 Study Design and Population 
This is a single-arm, open-label, Phase II study in KRAS-positive and KRAS-negative 
patients with stage IV (including pleural effusion) non-squamous NSCLC who have failed 
two lines of anti-cancer therapy. The study uses a two-stage design seeking to detect a true 
PFS rate of more than 35% in the overall (unselected) population and 40% within the KRAS 
tumor mutation positive and negative strata. Thirty evaluable patients (15 in each stratum) 
will be treated initially (Stage 1), with expansion to a maximum of 60 evaluable patients 
(Stage 2). An evaluable patient will have received at least one dose of antroquinonol and have 
a valid baseline tumor assessment. Enrollment will continue until the target number of 
evaluable patients has been enrolled. 
 
3.2 Study Treatments and Assessments 
Written informed consent must be obtained from all patients before initiating Screening. The 
Screening period will be up to 42 days in duration (Days -42 to -1). Following completion of 
all Screening assessments and confirmation of eligibility criteria, patients will receive 
antroquinonol 200 mg three times a day (t.i.d. at 8 hour intervals) on Day 0 for 12 weeks (one 
treatment cycle) or until documented evidence of disease progression, unacceptable toxicity, 
non-compliance or withdrawal of consent by the patient, or the investigator decides to 
discontinue treatment, whichever comes first. Study drug should be taken at 8 hour intervals. 
The time of study drug administration should be recorded in the patient diary. 
After the first 12 week treatment cycle, patients who are progression free or, in the opinion of 
their investigator, still deriving clinical benefit, will continue to receive up to three further (12 
week) treatment cycles with antroquinonol (Extension Phase). After completion of the fourth 
and last treatment cycle, patients will be eligible to receive further cycles of treatment with 
antroquinonol in a rollover protocol. Investigators should wait at least 7 days before initiating 
alternative treatment. 
Patients will attend study visits on Days 0, 14, 28, 42, 56 and 84 during the first 12 week 
treatment cycle and every 4 weeks during subsequent cycles (Extension Phase). The 
following procedures will be performed according to the schedule of assessments: physical 
examination, vital signs, 12 lead ECG, performance status, clinical laboratory tests, AEs, 
concomitant medication and patient compliance. 
Patients completing the 12 week treatment period (or the Extension Phase), and those 
discontinuing the study before Week 12 (or during the Extension Phase), will attend an End 
of Study (EOS) Visit 4 weeks after the last administration of study drug. 
Intensive PK sampling will be performed on Days 0 and 28 in all patients enrolled in Stage 1. 
Sparse PK sampling will be performed on Days 28, 42, and 56 in all patients enrolled in 
Stage 2. 
All patients who withdraw from the study before Week 12 (or during the Extension Phase) or 
who complete the 12 week treatment period (or the Extension Phase) will be followed up for 
survival status until 6 months from the date of last administration of study drug or death, 
whichever occurs first. 
Tumor assessments will be performed at Screening, Days 42 and 84 using the Response 
Evaluation Criteria in Solid Tumors (RECIST) criteria, version 1.1. Tumor assessments will 
be performed every 12 weeks during the Extension Phase. 


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The primary efficacy endpoint is progression free survival (PFS) rate at 12 weeks, which is 
defined as the proportion of patients alive and progression free at Week 12. Patients will be 
progression free if they have no evidence of progressive disease (defined according to 
RECIST guidelines, version 1.1) from the start of treatment to Week 12. The primary and 
secondary efficacy analyses will be conducted based on independent centralized assessment 
of ICON Medical Imaging (IMI). 
The details of the assessment schedule are described in the protocol and in the flow chart 
below. 
 
 


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Table 1 Flow Chart  
Study Procedure 
Screening
(- 42 days)
Visit (Day) 
End of 
Study 
(EOS) 
Visit2 
Extension
Phase3 
1
(0)
2 
(14)
3 
 (28)
4  
(42)
5  
(56)
6 
 (84)
Study visit window (days)
N/A 
0
± 3
± 3 
± 3
± 3 
± 3 
± 7 
± 7 
Informed consent1 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical & surgical 
history 
X 
 
 
 
 
 
 
 
 
Concomitant medication 
X 
X
X 
X 
X 
X 
X 
X 
X 
Inclusion/Exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
Tumor biomarkers4 
X 
 
 
 
 
 
 
 
 
Physical examination5 
X 
X
X 
X 
X 
X 
X 
X 
X 
Pregnancy test6 
X 
 
 
 
 
 
 
 
 
Vital signs7 
X 
X
X 
X 
X 
X 
X 
X 
X 
ECOG performance score
X 
X
 
X 
X 
X 
X 
X 
X 
12-Lead ECG 
X 
X
 
X 
X 
X 
X 
X 
X 
Clinical laboratory tests8 
X 
X
X 
X 
X 
X 
X 
X 
X 
Tumor assessments9 
X 
 
 
 
X 
 
X 
 X 
X 
Dispense study drug10 
 
X
 
X 
X 
X 
X 
 
X 
Drug accountability 
 
 
 
X 
X 
X 
X 
X 
X 
PK sampling11 
 
X
 
X 
X 
X 
 
 
 
AE assessment12 
 
X
X 
X 
X 
X 
X 
X 
X 
Patient compliance 
 
X
 
X 
X 
X 
X 
X 
X 
EORTC QLQ13 
 
X
 
 
X 
 
X 
X 
X 
ECOG: Eastern Cooperative Oncology Group; ECG: Electrocardiogram; PK: Pharmacokinetics; AE: 
Adverse Event; EORTC: European Organization for Research and Treatment of Cancer; QLQ: 
Quality of Life Questionnaire. 
1 Informed consent must be obtained before the patient undergoes any study-specific procedures. 
2 Patients completing the 12-week treatment period (or the Extension Phase) and those discontinuing the 
study before Week 12 (or during the Extension Phase) will attend an EOS Visit 4 weeks after the last 
administration of study drug. Tumor assessment does not need to be performed at the EOS Visit if this 
was conducted at the Day 84 Visit. For patients participating in the Extension Phase, the tumor assessment 
does not need to be performed at the EOS Visit if it has been assessed within 8 weeks of the EOS Visit. 
3 After the first 12-week treatment cycle, patients who are progression-free or, in the opinion of their 
investigator, still deriving clinical benefit, will continue to receive up to three further (12-week) treatment 
cycles with antroquinonol. After completion of the fourth and last treatment cycle, patients will be eligible to 
receive further cycles of treatment with antroquinonol in a rollover protocol. Investigators should wait at least 
7 days before initiating alternative treatment is administered. Patients completing or discontinuing the study 
during the Extension Phase will attend an EOS Visit 4 weeks after last administration of study drug. Patients 
will attend visits every 4 weeks (±7 days) during the Extension Phase. 


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4 Tumor tissue blocks will be obtained from archival material or from fresh biopsy during the Screening period 
to determine the tumor KRAS mutation status before the patient is enrolled. Tumor tissue will also be used to 
study arrays of genomic and proteomic markers of interest. 
5 Weight, height and body mass index (BMI) will be measured at Screening Visit only. 
6 A urine pregnancy test will be performed during the Screening Visit for women of child-bearing potential. 
This test can be repeated during the study if required by local regulations. 
7 Vital signs (respiratory rate, heart rate, blood pressure, and body temperature) will be performed at each 
visit. They will be obtained in the sitting position after the patient has rested for 5 minutes. The date and 
time of the assessment should be recorded. 
8 Hematology, chemistry, and urinalysis. 
9 Radiological and clinical tumor assessments will be performed at Screening, Day 42 and Day 84 using the 
RECIST criteria version 1.1. Evaluation during Screening must be performed within 14 (± 3) days of 
enrollment into the study. Tumor assessments will be performed every 12 weeks during the Extension 
Phase. 
10 All Screening procedures and laboratory results must be available and reviewed before the patient 
receives the first dose of study drug. Study drug should be taken at 8-hour intervals. The time of study 
drug administration should be recorded in the patient diary. 
11 Intensive PK sampling will be performed on Days 0 and 28 in all patients enrolled in Stage 1. Samples will be 
taken 30 minutes prior to and 0.5, 1, 2, 3, 4, 6, and 8 hours after the first dose on Day 0, and immediately 
before and 0.5, 1, 2, 3, 4, 6, and 8 hours after the first dose on Day 28. Sparse PK sampling will be performed 
on Days 28, 42, and 56 in all patients enrolled in Stage 2. At least two samples will be collected on each 
occasion, one of which will be a trough concentration (30 minutes prior to dosing and approximately 8 hours 
after the last dose on the prior day). At least one sample per patient will be timed to coincide with the peak 
concentration (approximately 3 hours after dosing). The remainder may be taken at any time during the 
dosing interval. 
12 Patients must be followed for AEs from the date of informed consent until at least 6 months after last dose of 
study drug or alternative treatment for NSCLC is started, whichever occurs first. In the event of serious or 
study drug-related toxicities, the patient will be followed until resolution or stabilization. Safety follow-up 
data may be collected by telephone contact every 2 months after the EOS Visit. 
13 Day 0 evaluation to be performed before the patient receives the first dose of study drug. 
 
 
  
 


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4. ANALYSIS VARIABLES 
The detailed derivation rules and/or censoring rules for each variable are specified in section 
6 along with analysis methods. Variables not referred to in this section, but collected 
throughout the study period, such as patient demographic data, study drug exposure, 
concomitant medication, will be summarized descriptively. 
The primary and secondary efficacy analyses will be based on the independent centralized 
assessment of medical images conducted by IMI. Tumor response, as assessed by the 
investigator at each site during the study, will be supportive. 
Primary Efficacy variable: 
The primary efficacy endpoint is PFS rate at 12 weeks. It is defined as the proportion of 
patients alive and progression-free to evaluable subject at Week 12. An evaluable patient who 
died from any cause or discontinued the study for any reason without a post-screening or 
Week 12 tumor assessment will be considered as failing to respond to treatment. 
Secondary Efficacy variable: 
The following secondary efficacy variables are defined in accordance with the RECIST 
guidelines, version1.1: 
Objective Response Rate (ORR): The ORR is defined as the proportion of patients whose best 
overall response is either CR or PR during the first 12-week treatment cycle.  
Disease Control Rate (DCR): The DCR is defined as the proportion of patients with a 
documented complete response (CR), partial response (PR) and stable disease (SD) during 
the first 12-week treatment cycle. 
Duration of Response (DOR): DOR is defined as the interval between the date of the first 
observation of tumor response (CR or PR) and the date of disease progression or death.  
Progression Free Survival (PFS): PFS is the time from date of first administration of study 
drug to date of first documentation of progression or death due to any cause, whichever 
occurs first. 
Overall survival (OS): Survival time will be calculated for all patients from the date of first 
administration of study drug to the date of death from any cause.  
Time to progression (TTP): Time to progression will be calculated for all patients from the 
date of first administration of study drug to the date of the first documented tumor 
progression.  
 
Pharmacokinetic variables:  
For stage 1, PK endpoints will be derived for intensively sampled PK profiles by 
noncompartmental methods and include: 
• 
Cmax: peak concentration 
• 
Ctrough: trough plasma concentration 
• 
Tmax: peak time 
• 
AUCτ: area under the plasma concentration-time curve over the 8-hour dosing interval 
• 
T½: terminal half-life 


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• 
Vz/F: apparent volume of distribution during elimination 
• 
CL/F: apparent oral clearance 
• 
T½,eff: effective half-life 
 
Safety variables: 
• 
Adverse Events recording and follow up 
• 
Vital Signs : blood pressure, heart rate, body temperature, respiratory rate 
 
ECOG performance status score 
• 
12-lead electrocardiogram (ECG) 
• 
Physical Examinations 
• 
Safety laboratory assessments : hematology, chemistry, urinalysis 
 
Patient Reported Outcome: 
Quality of life will be assessed using European Organization for Research and Treatment of 
Cancer (EORTC) QLQ C30 and the Module on Lung Cancer (QLQ-LC13), which is a 
validated instrument for assessing quality of life (QoL) in patients with lung cancer. The 
EORTC QLQ-C30 / EORTC QLQ-LC13 is comprised of a: 
• Global Health status scale 
• 5 functional scales(physical, role,  emotional, cognitive, and social) 
• 3 symptom scales(fatigue, nausea and vomiting, and pain) 
• Other single items from QoL questionnaire  
• Module designed specifically for lung cancer 
 
 


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5. SAMPLE SIZE AND POWER 
The study uses a two-stage design. Thirty evaluable patients (15 in each stratum) will be 
treated initially (Stage 1), with expansion to a maximum of 60 evaluable patients (Stage 2). 
Enrollment will continue until the target number of evaluable patients has been enrolled.  
The statistical design is based on literature published by Green and Dahlberg (1992)3, von 
Mehren et. al. (2012)4 and Hoang et. al. (2013)5 It is assumed that within each of the KRAS 
tumor mutation positive and negative strata, a PFS rate at 12 weeks of 40% and 35% overall 
(unselected) population will be of interest. Further testing will not be pursued if the PFS rate 
at 12 weeks is less than 15%.  
Initially, 15 evaluable patients are to be accrued within each stratum. If two or more patients 
are alive and progression-free within a stratum, then an additional 15 evaluable patients will 
be accrued to that stratum for a total of 30 evaluable patients. If nine or more patients are 
alive and progression-free within the 30 evaluable patients in the stratum then antroquinonol 
will be considered worthy of further study in that cohort. This design will allow a 
significance level of 2.8% and a power of 90.5% within each stratum.  
In addition to within-stratum hypothesis testing, this study is also designed to investigate the 
PFS rate at 12 weeks in the overall (unselected) population. If less than three patients are 
alive and progression-free in the first 20 evaluable patients, and the criterion for continuing 
the individual stratum are not met, then the accrual for all strata will be discontinued. 
Otherwise, a maximum of 40 additional evaluable patients will be entered (depending on 
whether any individual stratum is closed). Fifteen or more patients alive and progression-free 
out of the maximum 60 evaluable patients would warrant further study. The overall design 
has a significance level of 2.8% (probability of falsely declaring the regimen with a 15% PFS 
rate at 12 weeks to warrant further study) and power 95.6% (probability of declaring the 
regimen with a 35% PFS rate at 12 weeks in the overall population to warrant further study). 
 


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6. METHODS OF ANALYSIS AND PRESENTATION 
6.1 General Principles and Considerations 
Section 6 describes the algorithms, imputations and conventions that will generally apply to 
program manipulations of the data in order to prepare the proposed summary tabulations, and 
individual patient data listings. Unless otherwise indicated, these specifications apply to all 
analyses.  
Full details of the table, figure and listing outputs that will be produced are given in the 
document entitled “Golden Biotech-GHNSCLC-2-001_TFL Final v1 0 06Aug2014”. 
Appendix I lists the Tables (T), Figures (F) and Listings (L) (collectively TFLs) that will be 
generated for the DSMB (Data and Safety Monitoring Board). 
 
6.2 Presentation of Output  
Summaries will use the following descriptive statistics for continuous variables (n, mean, 
standard deviation [STD], median, minimum and maximum). The number of decimal places 
displayed for each statistical analysis will be determined as follows:  
1. 
Mean and median: one more than the number of decimal places allotted in the CRF 
2. 
Standard deviation: two more than the number of decimal places allotted in the CRF 
3. 
Minimum and Maximum: equal to the number of decimal places allotted in the CRF 
Qualitative variables will be presented as category counts and percentages. Percentages will 
be presented to one decimal place throughout. 
All dates will be displayed in DDMMMYYYY format. Visits will be referred to as shown in 
the protocol: “Baseline”, ‘Cycle1 Day1”, etc.  
Study day is defined relative to date of first administration of study drug. 
Data will be listed for all subjects. Individual subject data listings provide support for 
summary tables and serve as a data source substitute when a summary table is deemed either 
inappropriate or unnecessary. All data listings will be sorted by site number, subject number, 
visit date or study day unless otherwise specified. Throughout all data listings and summary 
tables, treatment will be labeled as Antroquinonol.   
 
6.2.1 Definition of Baseline and Visit Windows 
The baseline will be defined as the last value or measurement taken up to the first dosing of 
study drug, unless otherwise specified.  
Baseline tumor assessment is defined as a readable scan performed within 14 (± 3) study days 
prior to enrollment into the study by investigator at the site. Last Visit (Endpoint) is defined 
as the last on-therapy visit. Study day is defined relative to the date of the first administration 
of study drug as: 
Study day = date of assessment – date of first administration of study drug. 
The date of first administration of study drug will be Day0 as specified in the study protocol. 
For safety data (e.g. laboratory tests, vital signs, ECG etc.), nominal visit times will be used 
regardless of the study day.  


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Allowed windows for PK samples: 
 
Day 
Scheduled 
Time 
Relative to 
Dose (hour)
Time 
Window
Comment  
Stage 1
0 
-0.5 
 
Pre-dose sample 
0 
0.5 
± 5 min 
 
0 
1 
± 10 min
0 
2 
± 15 min
 
0
3
± 20 min
0 
4 
± 20 min
 
0 
6 
± 20 min
 
0
8
± 20 min
28 
-0.5* 
 
Pre-dose sample 
28 
0.5 
± 5 min 
 
28 
1 
± 10 min
 
28 
2 
± 15 min
 
28
3
± 20 min
28 
4 
± 20 min
 
28
6
± 20 min
28 
8 
± 20 min
 
Stage 2 
28 
-0.5* 
 
Trough 
28 
3 
± 1 hr 
Peak 
42 
-0.5* 
 
Trough 
42 
N/A 
 
Random** 
56 
-0.5* 
 
Trough 
56 
N/A 
 
Random** 
* Sample should be taken prior to current dose and approximately 8 hours after the 
prior dose. 
** Sample may be taken at any time during the dosing interval. 
 
Samples taken outside these windows may be used in the PK analyses provided that accurate 
dosing and sample time data are recorded and that any sampling time deviation does not 
meaningfully bias the PK parameters. 
 


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6.2.2 Missing data or partial date handling 
In the event that a partial date is provided for a tumor assessment conducted during the first 
12-week treatment phase and/or the extension phase the following rules will be adopted: 
 If day is missing, then the 15th day of the month will be assumed 
 If month or year are not available, the assessment will not be used 
Imputation Rules for Partial or Missing Stop Dates for adverse events and concomitant 
medications are detailed below. 
 If the month and year are present, impute the last day of that month. 
 If only the year is present, impute December 31 of that year. 
 If the stop date is entirely missing, assume the event or medication is ongoing. 
If a partial or complete stop date is presented along with checking the ‘ongoing’ or 
‘continuing’ box, then it will be assumed that the adverse event or concomitant medication 
stopped and the stop date will be imputed if partial. 
Imputation Rules for Partial or Missing Start Dates for adverse events and concomitant 
medications are detailed in Table 2. The following imputation rule will be applied, where 
applicable. 
Table 2 Imputation rules for partial or missing start dates 
Rule 
no. 
Criteria 1 
Criteria 2 
Imputation rule 
1 
partial start date (mmmyyyy) 
= 1st dose (mmmyyyy)  
or partial start date (yyyy) = 
1st dose (yyyy) 
partial stop date (yyyy) < 1st 
dose yyyy 
NA 
2 
partial start date (mmmyyyy) 
= 1st dose (mmmyyyy)  
or 
partial start date (yyyy) = 1st 
dose (yyyy) or 
start date = missing 
complete 
stop 
date 
(ddmmmyyyy) ≥ 1st dose 
(ddmmmyyyy)  
or 
partial stop date (mmmyyyy) ≥ 
1st dose (mmmyyyy)  
or 
partial stop date (yyyy) ≥ 1st 
dose (yyyy) or 
stop date = missing 
Impute the date 
of first dose 
3 
partial start date (mmmyyyy) not applicable to rule 2 
Impute the first 
day, i.e. 1, of the 
month 
4 
partial start date (yyyy) 
not applicable to rule 2 
Impute January 
1 of the year 


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Rule 
no. 
Criteria 1 
Criteria 2 
Imputation rule 
5 
start date = missing 
complete 
stop 
date 
(ddmmmyyyy) 
< 
1st 
dose 
(ddmmmyyyy)  
or 
partial stop date (mmmyyyy) < 
1st dose (mmmyyyy)  
or 
partial stop date (yyyy) < 1st 
dose (yyyy) 
Impute January 
1 of the stop 
year 
 
In all other instances, missing values will not be imputed. 
 
6.2.3 Version Numbers 
All analyses will be carried out using SAS® Version 9.13 or later. Data will be stored in 
Inform database. Adverse event and body/organ system coding will be performed using 
MedDRA version 17.0. Prior/concomitant medication coding will utilize WHO Drug March 
2014E. 
 
6.3 Analysis Sets 
6.3.1 Safety Population 
The safety population includes all patients who received at least one dose of study drug. 
This population will be used for the analysis of safety data. 
 
6.3.2 Evaluable Population 
The evaluable population will include patients who in safety population and meet all 
eligibility criteria as well as having a valid baseline tumor assessment. 
A valid baseline assessment is defined as a readable scan (one in which the images are of 
high enough quality to permit accurate assessment of the tumor) performed within 14 (± 3) 
days prior to enrollment into the study. 
This will be the primary analysis population for primary efficacy analysis. 
 
6.3.3 Full Analysis Set (FAS) 
The FAS will consist of patients in the evaluable population who has at least one post-
baseline tumor assessment. 
This analysis population will be used for supportive population of primary efficacy analyses 
and used for all secondary efficacy analyses. 
 


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6.3.4 Per-Protocol Set (PPS) 
The PPS is a subset of patients in FAS who do not have major protocol violations. Major 
protocol violations will include (but are not limited to) the following:  
 
Subject did not meet all inclusion/exclusion criteria 
 
Use of prohibited/excluded concomitant medication/procedure that may impact 
patient safety or the primary study objective 
 
Error in administration of study drug – Potential impact on subject safety or primary 
study objective 
Major protocol deviations will be discussed and agreed during the Data Review Meeting.  
This analysis population will be used for supportive population of primary efficacy analyses 
and used for all secondary efficacy analyses. 
 
6.3.5 PK Population 
The PK population will consist of patients in the first stage who have an evaluable PK profile, 
defined as a profile from which at least one of the PK parameters stated as endpoints can be 
estimated, and no protocol deviations that would affect the PK of antroquinonol. 
 
6.3.6 Population-Based PK (PopPK) Population 
The PopPK population will consist of enrolled patients with at least two plasma 
concentrations and sufficient and reliable dosing histories. 
 
6.3.7 Patient Reported Outcome (PRO) Population 
The PRO population will consist of all patients who have completed the QoL Questionnaire 
on Day 0 and on at least one occasion after the first administration of study drug. 
This population will be used for the analysis of patient reported outcome data. 
 
6.4 
Major Protocol Violations/Deviations 
Major protocol violations/deviations will be defined as any event or behavior of the patient or 
the investigator, which makes the evaluation of the primary objective of the protocol 
impossible or unreliable. Protocol deviation criteria will be described in the document 
entitled “Golden Biotech_Protocol Deviations Criteria_v1.0_28Jul14”. 
Protocol violations/deviations will be defined during the Data Review Meeting of the study 
before final database lock.  
 
6.5 Disposition 
The number of patients screened, enrolled, treated, on-going, completed or discontinued for 
first 12-week treatment phase and extension phase will be summarized for the overall 
(unselected) population and by KRAS mutation status(positive/negative)..  
Patients who discontinue from the treatment phase and/or the extension phase will be 
summarized by their primary reason for discontinuation for the overall population and by 


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KRAS mutation status. 
Screen failures (reason for failure) will be summarized. Supportive listings will be provided. 
Data on inclusion/exclusion criteria and protocol deviations will also be reported. 
A listing of protocol violations will be summarized by KRAS mutation status. The listing will 
include a variable indicating whether the violation is considered as key or non-key. 
 
6.6 Demographics and Baseline Characteristics 
Patient demographics and baseline characteristics will be summarized for the safety and the 
all evaluable population.  
Demographic data (age at consent as continuous and categorized into <40 years, ≥40-<65 
years and ≥65 years, sex, race, ethnicity, region, smoking status, disease stage at initial 
diagnosis) will be summarized.  
ECOG Performance Status at screening will be summarized. 
Medical history and baseline signs and symptoms and previous therapy for treatment of 
NSCLC will also be summarized by KRAS mutation status. An overall summary of prior 
therapy will be produced which will include the number of prior chemotherapy and whether 
subject had prior surgery, radiotherapy and other regimens will be summarized by KRAS 
mutation status.  
Number of patients and percentage of biomarker data including KRAS mutation status, 
EGFR, ALK and ROSI will be summarized for overall stratum. 
 
6.7 
Prior and Concomitant medication 
Medication history and concomitant medication will be summarized by KRAS mutation 
status and WHO Drug preferred term for the Safety population.  
Medication will be classified as: 
 
Prior medications : 
 
Those started and stopped prior to the first dosing (Day 0) 
 
Concomitant medications : 
 
Those started prior to and on-going at the first dosing (Day 0), or 
 
Those started after or equal to the first dosing (Day 0). 
If medication could not be classified due to incomplete or partial start and/or stop dates, it 
will be assumed to be concomitant medication. 
 
6.8 Treatment Compliance and exposure 
Study drug compliance and exposure during treatment phase and extension phase will be 
summarized by KRAS mutation status.  
For each visit, except Visit 2, the compliance will be calculated by: 
[(Capsules actually used) ÷ (number of days patients exposed to study drug * planned number 
of capsules per day)]  


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The number of days patients exposed to study drug is calculated as: 
[Date of last dose -Date of first dose + 1]. 
Patients who undergo dose modifications will have their treatment compliance calculated by: 
 (Original dose [(Capsules actually used) ÷ (number of days patients exposed to study drug* 
planned number of capsules per day for each day patient was on original dose)]) + (Modified 
Dose [(Capsules actually used) ÷ (number of days patients exposed to study drug* planned 
number of capsules per day for each day patient was on modified dose)]) 
The extent of exposure to Antroquinonol will be characterized by the number of administered 
cycles, cumulative dose (mg), dose intensity (mg/week). Dose intensity will be calculated by 
dividing the total received dose (mg) of the study drug by the number of weeks of treatment. 
The number of dose adjustments together with each reason will be summarized by KRAS 
mutation status. 
6.9 Efficacy Analysis 
Except for the primary efficacy analysis, there will be no formal statistical testing. All data 
will be summarized and listed descriptively. All efficacy endpoints will be evaluated for the 
overall population and by KRAS mutation status. 
The primary and secondary efficacy analyses will be based on the independent centralized 
assessment of medical images conducted by IMI. The Independent Review Charter is 
provided in the Appendix II. 
A sensitivity analysis, based on the local (investigator) assessment will also be conducted and 
summarized. 
The same response assessment rule will be used for the centralized and local (investigator) 
review. For example, tumor assessment dates are defined as: 
- 
Progression date: Radiological assessments for a given visit occur over a series of 
days rather than the same day. The Date of Progression will be the date of the first 
scan, regardless of modality. 
- 
Response date: Date of Initial Response is defined as the date when either level of 
response (PR or CR) first appears as a timepoint response on CT or MRI tumor 
assessment imaging. When multiple scan dates are associated with the timepoint for 
which a response was first recorded, the latest scan date associated with that 
timepoint will be the Date of First Response 
 
6.9.1 Primary Endpoint 
As stated in section 4, the primary endpoint is the PFS rate at 12 weeks. It is defined as the 
proportion of patients alive and progression-free to evaluable subject at Week 12. Patients 
will be progression-free if they have no evidence of progressive disease (defined according to 
RECIST guidelines, version 1.1) from the date of first administration of study drug to Day 84 
(±3). Study day will be computed by [date of assessment – the first date of administration of 
study drug]. An evaluable patient who died from any cause or discontinued the study for any 
reason without a post-screening or Week 12 tumor assessment will be considered as failing to 
respond to treatment.  
The centralized review for the evaluable population will be primary for hypothesis testing. 
The PFS rate at week 12 along with a two-sided 95% Clopper–Pearson exact confidence 


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interval will be provided for the overall evaluable population and each KRAS mutation 
stratum.  
The supportive analysis will performed on the FAS and PPS, as for the evaluable population. 
The time window used for the evaluable population will be applied.  
 
6.9.2 Secondary Endpoint(s) 
All secondary efficacy endpoints will be evaluated for the FAS and PPS. Analyses based on 
the both central and local (investigator) review will be summarized. 
 
Objective Response Rate (ORR) 
Tumor response will be evaluated according to the RECIST guidelines version1.1. The 
response assessment categories are CR, PR, SD, and progressive disease (PD), not evaluable 
(NE). The best overall response will be the best response achieved during the first 12-week 
treatment phase.  
The ORR is defined as the number of patients whose best overall response is either CR or PR 
according to RECIST 1.1 divided by the number of patients in the analysis population. For 
the analysis of response, patients with missing response data will be reported and 
distinguished from non-responders, and included in the denominator when calculating 
percentages.   
Exact Pearson-Clopper 2-sided 95% confidence limits for the tumor response rates in each 
arm will be calculated. 
The number and percentage of patients assigned to each best overall response category (CR, 
PR, SD, PD, NE) will be summarized. 
For each patient, the maximum decrease in sum of longest diameter of target lesions will be 
plotted.  Patients in each category of best overall response (i.e. CR, PR, SD, and PD) will be 
represented in different colors.  A separate plot will be produced by KRAS mutation status.     
 
Disease Control Rate (DCR) 
The DCR is defined as the proportion of patients with a documented CR, PR and SD during 
the first 12-week treatment cycle according to RECIST 1.1. 
DCR will be analyzed and presented together with ORR. 
 
Duration of Response (DOR) 
DOR is defined as the time from first documented evidence of CR or PR (whichever status is 
recorded first) until the first documented sign of disease progression or death due to any 
cause.  For patients in the subset of responders who do not progress or die, DOR will be 
censored.  
DOR (days) = Date of progression/ death/ censoring – Response date +1.   
The table below will be used for calculating the DOR. 


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Situation 
End Date 
Outcome 
Documented PD during the study
Date of the first assessment of the 
series of the tests that determined PD
Eventa 
Death during the study before PD
Date of death 
Eventa 
Discontinued due to PD, but no 
documented PD  
Date of last tumor assessment before 
discontinuation 
Censored 
Discontinued due to clinical 
progression per investigator 
Date of last tumor assessment before 
discontinuation 
Censored 
Treatment discontinuation for 
reason other than PD or death 
Date of last tumor assessment  
Censored 
New anticancer treatment started 
Date of last tumor assessment before 
start of new treatment 
Censored 
Death or PD after one or more 
missed tumor assessments 
Date of the last assessment before 
missed assessments 
Eventa 
Patients still on treatment without 
PD as of data cut-off 
Date of last tumor assessment  
Censored 
 a - Earliest date among the three dates is used in calculating the DOR. 
DOR will be summarized using Kaplan-Meier method.  The Kaplan-Meier estimate of the 
median DOR and first and third quartiles will be presented with 95% confidence intervals for 
the subset of responders. Kaplan-Meier curve will be presented. 
If the number of patients with a documented CR or PR is less than 10 subjects for each 
stratum then only descriptive statistics or listings will be presented. 
 
Progression Free Survival (PFS) 
PFS is the time from date of first administration of study drug to date of first documentation 
of progression or death due to any cause. Date of first documentation of progression can be 
based on the centralized or local (investigator) review.  
PFS (days) = Date of progression/ death/ censoring – Date of first administration of study 
drug + 1. 
The table below will be used for calculating the PFS. 


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Situation 
End Date 
Outcome 
Documented PD during the study
Date of the first assessment of the 
series of the tests that determined 
PD 
Eventa 
Death during the study before PD 
Date of death 
Eventa 
Discontinued due to PD, but no 
documented PD  
Date of last tumor assessment 
before discontinuation 
Censored 
Discontinued due to clinical 
progression per investigator 
Date of last tumor assessment 
before discontinuation 
Censored 
No baseline assessments  
Date of first administration of 
study drug  
Censored 
Treatment discontinuation for 
reasons other than PD or death, 
and no post-baseline tumor 
assessments 
Date of first administration of 
study drug 
Censored 
Treatment discontinuation for 
reasons other than PD or death 
with post-baseline tumor 
assessments 
Date of last tumor assessment  
Censored 
New anticancer treatment started 
prior to disease progression 
Date of last tumor assessment 
before start of new treatment 
Censored 
Death or PD after one or more 
missed tumor assessments 
Date of the last assessment before 
missed assessments 
Eventa 
Patients still on treatment without 
PD as of data cut-off 
Date of last tumor assessment  
Censored 
 a - Earliest date among the three dates is used in calculating the PFS. 
PFS will be summarized using the Kaplan-Meier method. The Kaplan-Meier estimate of the 
median PFS time and first and third quartiles will be presented with 95% confidence intervals. 
The 12, 24, 36, and 48 week PFS rates will also be provided with 95% confidence intervals. 
Kaplan-Meier curve will be presented.  
The number and percentage of subjects in the overall (unselected) group and by KRAS 
mutation status who have progressed or died at 12 weeks, 24 weeks, 36 weeks and 48 weeks 
will be summarized along with the number and percentage of censored subjects (follow-up 
ended or follow-up ongoing). 
 
Overall Survival (OS) 
OS is defined as the time from date of first administration of study drug until the date of 
death due to any cause.  For patients who are lost to follow-up or who are alive at the date of 
data cut-off, the time to death will be censored at the time of last contact. 
OS (days) = Date of death/censoring – Date of first administration of study drug + 1. 
The table below will be used for calculating the OS. 
 


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Situation 
End Date 
Outcome 
Death during study
Date of death 
Event 
Patient still alive at data cut-off 
Date last known to be alive 
Censored 
Patient lost to follow-up before 
data cut-off 
Date last known to be alive 
Censored 
OS will be summarized using the Kaplan-Meier method. The Kaplan-Meier estimate of the 
median survival time and first and third quartiles will be presented with 95% confidence 
intervals.  The 12 and 48 week OS rates will also be provided with 95% confidence intervals. 
Kaplan-Meier curve will be presented. 
 
Time to Progression (TTP) 
The analysis and censoring rule for TTP will be performed as explained under DOR.  
TTP (days) = Date of disease progression/ censoring – Date of first administration of study 
drug + 1. 
TTP will be summarized using the Kaplan-Meier method. The Kaplan-Meier estimate of the 
median TTP and first and third quartiles will be presented with 95% confidence intervals.  
Survival rate of 12, 48 weeks will also be provided with 95% confidence intervals. Kaplan-
Meier curve will be presented. 
 
6.10 PK Analysis 
6.10.1 Noncompartmental Pharmacokinetic Analysis (NCA) 
For intensively sampled PK profiles from the PK population, pharmacokinetic parameters 
will be calculated from the concentration-time data using noncompartmental techniques 
(Phoenix WNL® Version 6.2.1 [or later], Pharsight Corp, St. Louis, MO). Calculation will be 
based on the actual sampling times recorded during the study. 
The following PK parameters will be determined after doses of antroquinonol on Days 0 and 
28, as appropriate: 
Variable 
Definition 
AUCτ 
Area under the plasma concentration-time curve during a dosing interval (τ) 
AUC0-∞ 
Area under the concentration-time curve from time zero extrapolated to 
infinity, calculated as AUC0-t + (Clast / λz) where AUC0-t is AUC from time 
zero (pre-dose) to time of last quantifiable concentration, Clast is the last 
temporal predicted plasma concentration (Day 0 only), and λz is the terminal 
phase elimination rate constant 
Cmax 
Maximum observed plasma concentration 
Tmax 
Time at which the Cmax was observed 
T½ 
Apparent elimination half-life, calculated as ln(2)/λz 
T½,eff 
Effective half-life calculated as τ×log(2)/log(RAUC/(RAUC-1)) (Day 28 only) 


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CL/F 
Apparent oral clearance, calculated as Dose/AUC0-∞ on Day 0 and Dose/AUCτ 
on Day 28 
Vz/F 
Volume of distribution during elimination, calculated as (CL/F)/λz 
Ctrough 
Trough concentration at the end of each dosing interval (i.e. τ hours after 
dosing) 
RAUC 
accumulation ratios for AUCτ, calculated as AUCτ on Day 28 divided by 
AUCτ on Day 0 
Following administration, Cmax and Tmax will be obtained directly from the experimental 
observations. If multiple maxima occur at equal concentrations, the first temporal value will 
be taken. 
AUC will be calculated using the linear/log trapezoidal rule, using actual elapsed time values. 
The number of data points included in the regression for determination of λz and T½ will be 
determined by visual inspection, but a minimum of 3 data points in the terminal phase, 
excluding Cmax, will be required to estimate λz. The λz values (and consequently T½, CL/F, 
Vz/F, and AUC0-∞ values) will be considered unreliable estimates if the time period over 
which an individual λz was estimated is less than twice the resultant T½ or if the adjusted 
coefficient of determination ‘Rsq’ is less than or equal to 0.8. 
The proportion of AUC0-∞ due to extrapolation (AUCextr) will also be calculated, and 
expressed as a percentage. The value of AUCextr should be less than or equal to 20% of the 
AUC0-∞ to be considered to be well estimated. If this proportion is any higher, then the values 
of AUC0-∞, CL/F, and Vz/F will be considered unreliable and therefore excluded from the 
analysis. 
6.10.2 Treatment of Outliers 
Individual antroquinonol plasma concentration-time points, if considered anomalous, may be 
excluded from the analysis at the discretion of the pharmacokineticist following a review of 
the available documentation (bioanalytical report, CRF, etc.). Any such exclusion will be 
discussed with the sponsor and clearly outlined in the study report. 
Entire individual treatment profiles for a subject may be excluded following review of the 
available documentation and discussion with the sponsor. However, results of analysis with 
and without the excluded profiles will be presented in the study report. Any such exclusion 
will be clearly listed in the study report along with justification for exclusion. 
6.10.3 Non-Quantifiable Concentrations 
All plasma concentrations reported as No Result (NR) values will be treated as missing and 
will appear in the data set as “.”. 
For the purpose of calculating AUC, when 2 consecutive values less than the lower limit of 
quantification (LLOQ) are encountered after Tmax, these and all subsequent values will be 
excluded from the analysis. Values less than LLOQ that are encountered prior to Tmax will be 
set to 0. When single embedded missing values occur, they will be excluded from the 
analysis. For calculation of summary concentrations, <LLOQ will be set to 0. 


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6.10.4 PopPK Analysis 
If possible, PK data from all patients (Stages 1 and 2) in the PopPK population will be 
analyzed using nonlinear, mixed-effects methods and post hoc estimates of antroquinonol 
exposure (i.e., Cmax, Ctrough, and AUCτ) computed for exploration of potential exposure 
response relationships. Full details of the PopPK analysis will be provided in a separate 
modeling and simulation analysis plan (MSAP). If performed, results from the PopPK 
analysis will not be reported in the clinical study report (CSR), but will be the subject of a 
separate PopPK report. 
6.10.5 Reporting of Concentrations and PK Parameters 
Intensively sampled plasma concentration-time data for antroquinonol will be listed and 
summarized descriptively. The following descriptive statistics will be calculated at each of 
the sampling times: n, mean, median, standard deviation (STD), geometric mean, coefficient 
of variation (CV[%]), 25th percentile, minimum, 75th percentile, and maximum. 
Individual and mean (+STD) plasma concentration-time profiles of antroquinonol will be 
presented graphically on a semi-logarithmic and a linear scale.  
Pharmacokinetic parameters of antroquinonol will be listed by subject and summarized 
descriptively by study day for the PK population. The following descriptive statistics will be 
provided: n, arithmetic mean, STD, median, min and max and 95% confidence interval. Only 
n, median, min and max will be reported for Tmax. In addition, geometric means and between-
subject CV will be calculated for AUCτ, AUC0-∞, Cmax, Cτ, T½, T½,eff, CL/F, Vz/F, and Ctrough. 
A box plots will be used to graphically compare Cmax and CL/F on Days 0 and 28. 
Sparsely sampled plasma concentration data will be listed. Nominal trough concentrations 
within subject will be summarized as the arithmetic mean and listed along with observed 
concentration data. 
 
6.11 Patient Reported Outcome 
The EORTC QLQ-C30 is comprised of a global health status scale, five functional scales 
(physical, role, emotional, cognitive and social) and three symptom scales (fatigue, nausea 
and vomiting, pain) and six single items (dyspnea, insomnia, appetite loss, constipation, 
Diarrhea and financial difficulties).  
The QLQ-LC13 includes questions assessing lung cancer-associated symptoms (cough, 
hemoptysis, dyspnea and site specific pain), treatment-related side effects (sore mouth, 
dysphagia, peripheral neuropathy and alopecia) and pain medication. 
Descriptive statistics will be presented for both absolute scores and changes from baseline 
(Day 0) for EORTC QLQ-C30 and QLQ-LC13 at each nominal time. Scores will be plotted 
for Dyspnea from QLQ-LC13. 
The questionnaire will be scored according to the algorithm described in the QLQ-C30 
scoring manual6. All scales are scored on categorical scales and linearly transformed to 0-100 
scales where: 
• 
a high score for a functional scale represents a high or healthy level of functioning 
• 
a high score for the global QoL scale represents a high level of quality of life 


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• 
a high score for a symptom scale or item represents a high level of symptomatology or 
problems 
Details of the scoring algorithms can be seen in Appendix III 
 
6.12 Safety Analysis 
All patients who are treated with at least one dose of study drug will be evaluated for safety. 
Safety data will be summarized for the overall (unselected) population and by KRAS 
mutation status. There will be no formal statistical analysis of safety data. 
 
6.12.1 Adverse Events 
Adverse Events (AEs) collected for the duration of the study from the time the subject signs 
the informed consent will be classified as per the MedDRA, graded using the National 
Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 
4.03. Based on the timing of each AE relative to the date of the first study procedure or first 
dose of study drug, whichever occurs first, it will be classified as being a Pre-Treatment AE 
or a Treatment-Emergent AE, according to the following definitions: 
• Pre-Treatment Adverse Events are defined as any AE, whose onset occurs prior to 
undergoing the first study procedure or receipt of first dose of study drug (whichever 
occurs first) 
• Treatment-Emergent Adverse Events (TEAE) are defined as any AE whose onset occurs 
or intensity worsens after undertaking the first study procedure or first dose of study drug 
(whichever occurs first). 
AEs will be coded using the MedDRA AE dictionary, which is an adverse event reporting 
system which allows the grouping of adverse events and the classification of adverse events 
into a system organ class and preferred term. Events will be graded for severity using NCI-
CTCAE, version 4.03. In addition, the relationship of each AE to study drug, study drug will 
also be assessed by the investigator. For each of these categories, the causality will be 
assumed as “Related” where the causality outcome is missing or where it cannot be 
determined. 
The following summary tables will be prepared: 
• Overview of AEs: 
o Number of subjects with any treatment-emergent AEs, related study drug 
treatment-emergent AEs, Grade 3 or 4 or 5 treatment emergent AEs, 
treatment-emergent AEs leading to withdrawal. 
o Serious treatment-emergent AEs, related study drug serious AEs, treatment-
emergent AEs leading to withdrawal. 
o Deaths. 
• Incidence of treatment-emergent AEs 
• Incidence of treatment-emergent AEs related to study drug 
• Drug-related treatment-emergent AEs 
• Treatment-emergent AEs leading to discontinuation 


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• Incidence of serious treatment-emergent AEs  
• Incidence of serious AEs related to study drug 
All AEs will be presented in a listing, with a flag to indicate their classification based on the 
categories as pre-TEAE and TEAE as described earlier in this section. In addition, separate 
listings for TEAEs leading to study drug discontinuation, serious TEAEs and AEs resulting in 
death will be presented. 
All AE data will be presented using the Safety population. All summaries of AEs will include 
counts subjects. For counts of subjects, subjects will only be counted once per preferred term 
and once per system organ class. In the case that a patient has multiple events with different 
intensity, severity etc., the worst case will be used in data presentation. 
6.12.2 Deaths 
The incidence and reasons for death will be presented using frequency counts and 
percentages.  
 
6.12.3 Clinical Laboratory Evaluations 
All laboratory parameters will be reported in SI units using the safety population. Laboratory 
data will be summarized at each visit for the overall (unselected) population and by KRAS 
mutation status. The final on therapy value (End of Study) will be summarized for the overall 
(unselected) population and by KRAS mutation status. 
Continuous laboratory parameters will be summarized by absolute values and change from 
baseline. 
Laboratory results will be classified according to NCI-CTCAE (version 4.03) where the 
grading criteria for the test are available by NCI-CTCAE. Incidence of maximum NCI-
CTCAE grade under treatment and shifts in toxicity grading from treatment start to highest 
grade will be displayed. Only subjects with post-baseline laboratory values will be included 
in these analyses.  
 
6.12.4 Vital Signs 
Vital signs data (heart rate, body temperature, systolic and diastolic blood pressure) and 
changes from baseline (i.e. last measurement before randomization) will be summarized 
descriptively.  
 
6.12.5 12-Lead ECGs 
ECG data (Heart rate, RR, QRS, QT, QTc and QTc) will be summarized descriptively.  
The ECG interpretation (normal, abnormal not clinically significant or abnormal clinically 
significant) will be summarized at each visit compared with baseline using a shift table. 
 
6.12.6 Physical Examinations 
The baseline results of the physical examination will be presented. Clinically significant, 
abnormal findings from the examinations will be reported as AEs. Separate summaries of the 
physical examination during and after treatment will therefore not be provided.  


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6.13 Subgroup Analysis 
Exploratory subgroup analysis will be conducted to investigate if the following factors 
influence PFS rate at 12 weeks. Subgroup analysis will be conducted on the evaluable 
population for PFS. 
- 
Sex (Male vs. Female) 
- 
Smoking History (Yes vs. No) 
- 
Race (Asian, American Indian or Alaska Native, Black or African American, White, 
Other) 
- 
Prior chemotherapy (Yes vs. No) 
- 
Baseline ECOG status (0 vs. 1/2) 
- 
EGFR (positive vs. negative) 
- 
ALK (positive vs. negative) 
- 
ROSI (positive vs. negative) 
- 
Stage (Stage1 vs. Stage2) 
 
6.14 Interim Analysis and Data and Safety Monitoring Board (DSMB) 
An independent Data and Safety Monitoring Board (DSMB) will be established to monitor 
safety and efficacy. Further details are provided in the DSMB charter. Appendix I lists the 
outputs that will be provided.  
The independent centralized review will be used for the interim analysis.  
An interim analysis will be performed when 20 patients overall and when 15 patients within 
each stratum are evaluable for the primary endpoint, PFS rate at 12 weeks. As described in 
Section 5, if less than two patients are alive and progression-free within a stratum, and then 
the accrual for that stratum will be discontinued. Otherwise, a maximum of 15 additional 
evaluable patients will be accrued to that stratum for a total of 30 evaluable patients. 
Furthermore, if less than three patients in the overall (unselected) population are alive and 
progression-free in the first 20 evaluable patients, and the criterion for continuing the 
individual stratum are not met, then the accrual for all strata will be discontinued. Otherwise, 
a maximum of 40 additional evaluable patients will be entered (depending on whether any 
individual stratum is closed). 
 
6.15 Analysis for Extension Phase 
After the first 12-week treatment cycle, patients who are progression-free or, in the opinion of 
their investigator, still deriving clinical benefit, will continue to receive up to three further 
(12-week) treatment cycles with antroquinonol in the Extension Phase. 
The analyses specified in this document apply to the first 12-week cycle and the Extension 
Phase. When all patients have completed the Extension Phase, all of the analyses specified in 
the SAP will be conducted, as appropriate.  
 


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6.16 Changes to Planned Analyses 
None.  


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7. REFERENCES 
1. ICH Topic E3: Structure and Content of Clinical Study Reports (CPMP/ICH/137/95-
adopted December 1995). 
2. ICH Topic E9: Statistical Principles for Clinical Trials (CPMP/ICH/363/96 – adopted 
March 1998).  
3. Green S. J. and Dahlberg S (1992). Planned Versus Attained Design in Phase II 
Clinical Trials. Statistics in Medicine 11:853-862. 
4. von Mehren M., Rankin C., Goldblum J.R., Demetri G.D., Bramwell V., Ryan C.W., 
and Borden E. (2012). Phase 2 Southwest Oncology Group-Directed Intergroup Trial 
(S0505) of Sorafenib in Advanced Soft Tissue Sarcomas. Cancer 118:770-776. 
5. Hoang T, Campbell TC, Zhang C, Kim KM, Kolesar JM, Oettel KR, et al. Vorinostat 
and bortezomib as third-line therapy in patients with advanced non-small cell lung 
cancer: a Wisconsin Oncology Network Phase II study. Invest New Drugs. 2013 June; 
DOI 10.1007/s10637-013-9980-5. 
6. EORTC QLQ-C30 Manuals, Reference Values and Bibliography 
http://www.eortc.be/home/qol/ 
 


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APPENDIX I: DSMB TFLS SPECIFICATIONS 
The following outputs will be produced for the DSMB for safety monitoring: 
 
Table Number*
Subject Disposition, All subjects 
14.1.1.2 
Subject Discontinuation, Safety population 
14.1.1.3 
Demographic and Baseline Characteristics, Evaluable population 
14.1.2.1.1 
Demographic and Baseline Characteristics, Safety population 
14.1.2.1.2 
Discontinuation Due to Adverse Events , Safety population 
14.3.3.3 
Progression Free Survival rate at 12 week, Evaluable population 
14.3.2.1 
Progression Free Survival Rate at 12 Week by Region, Evaluable 
Population 
14.3.2.1.3.7 
Progression Free Survival Rate at 12 Week by Race, Evaluable 
Population 
14.3.2.1.3.8 
Kaplan-Meier Plot of Progression Free Survival (PFS), Full Analysis Set 
14.2.2.1 
Objective Response Rate, Evaluable population 
14.3.2.2.1 
Summary of Treatment-Emergent Adverse Events (All Causality) , Safety 
population 
14.3.3.1.1 
Treatment-Emergent Adverse Events by System Organ Class, Preferred 
Term (All Causality) , Safety population 
14.3.3.1.2 
Incidence and Severity of Treatment-Emergent Adverse Events by 
System Organ Class, Preferred Term (All Causality) , Safety population 
14.3.3.1.3 
Treatment-Emergent Serious Adverse Events by System Organ Class, 
Preferred Term (All Causality) , Safety population 
14.3.3.1.6 
Laboratory Observed Results and Changes from Baseline – Hematology, 
Safety population 
14.3.4.1.1 
Laboratory Observed Results and Changes from Baseline – Biochemistry, 
Safety population 
14.3.4.2.1 
ECG Data and Changes from Baseline, Safety Population 
14.3.4.3.1 
Overall Objective Tumor Assessment 
16.2.6.6 
Listing of Adverse Events with Toxicity Grade 3/4/5 
16.2.7.1.2 
Listing of Serious Adverse Events 
16.2.7.1.3 


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Table Number*
Listing of Deaths 
16.2.7.2 
12-lead Electrocardiogram Data 
16.2.8.4 
*Table number can be modified as per the final TFLs mocks for CSR 
 
 


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APPENDIX II: INDEPENDENT REVIEW CHARTER 
 
GHNSCLC2001_IR
C_ Final1p0_201402 
 
 


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APPENDIX III: QOL SCORING CONVENTIONS  
All of the scales and single-item measures of the QLQ-C30 and QLQ-LC13 range in score 
from 0 to 100. A high scale score represents a higher response level. Thus a high score for a 
functional scale represents a high/healthy level of functioning, a high score for the global 
health status/QoL represents a high QoL, but a high score for a symptom scale/item 
represents a high level of symptomatology/problems. 
The principle for scoring these scales is the same in all cases: 
1. Estimate the average of the items that contribute to the scale; this is the raw score. 
(
)
RS
I
I
I
n
n
=
+
+
+
1
2
...
 
, where itemts , , …  are included in each scale 
2. Use a linear transformation to standardize the raw score, so that scores range from 0 to 
100. 
Functional scales:   
S = {1 – [(RS – 1)/range]}*100 
Symptom scales/items: 
S = {(RS – 1)/range}*100 
Global health status/QoL: 
S = {(RS – 1)/range}*100 
where range is the difference between the maximum possible value of RS and the minimum 
possible value.  
The QLQ-C30 has been designed so that the items at the beginning (for example, Q1 to Q28), 
are all scored 1 to 4, and contribute to one set of scales to different sets of scales; for these 
range = 3. The items Q29, Q30, scoring 1 to 7, contribute to the global health status / QoL 
which therefore has range = 6. Details on the construction of individual scales are provided in 
the table below. 
Scoring of the EORTC QLQ-C30: 
 
Abbreviation
Number 
of items 
Items  
(QLQ question 
numbers) 
Item 
range 
Functional scales 
Physical functioning 
PF 
5 
1 to 5 
3 
Role functioning 
RF 
2 
6, 7 
3 
Emotional functioning 
EF 
4 
21 to 24 
3 
Cognitive functioning 
CF 
2 
20, 25 
3 
Social functioning 
SF 
2 
26, 27 
3 
Global health status / QoL 
Global health status/QoL 
QL 
2 
29, 30 
6 
Symptom scales / items
Fatigue 
FA 
3 
10, 12, 18 
3 
Nausea and vomiting 
NV 
2 
14, 15 
3 


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Abbreviation
Number 
of items 
Items  
(QLQ question 
numbers) 
Item 
range 
Pain 
PA 
2 
9, 19 
3 
Dyspnoea 
DY 
1 
8 
3 
Insomnia 
SL 
1 
11 
3 
Appetite loss 
AP 
1 
13 
3 
Constipation 
CO 
1 
16 
3 
Diarrhoea 
DI 
1 
17 
3 
Financial difficulties 
FI 
1 
28 
3 
 
The QLQ-LC13 module incorporates one multi-item scale to assess dyspnoea, and a series of 
single items assessing pain, coughing, sore mouth, dysphagia, peripheral neuropathy, 
alopecia, and haemoptysis. The scoring approach for the QLQ-LC13 is identical in principle 
to that for the symptom scales single items of the QLQ-C30. Details on the construction of 
individual scales are provided in the table below. 
Scoring of the EORTC QLQ-LC13: 
 
Abbreviation
Number 
of items 
Items 
(QLQ question 
numbers) 
Item 
range 
Symptom scales / items 
Dyspnoea 
LCDY 
3 
3,4,5 
3 
Coughing 
LCCO 
1 
1 
3 
Haemoptysis 
LCHA 
1 
2 
3 
Sore mouth 
LCSM 
1 
6 
3 
Dysphagia 
LCDS 
1 
7 
3 
Peripheral neuropathy 
LCPN 
1 
8 
3 
Alopecia 
LCHR 
1 
9 
3 
Pain in chest 
LCPC 
1 
10 
3 
Pain in arm or shoulder 
LCPA 
1 
11 
3 
Pain in other parts 
LCPO 
1 
12 
3 
 


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SAS Commands for scoring the QLQ-C30/LC13 is provided in “Usage of statistical packages” 
section (page 15) on EORTC QLQ-C30/LC13 Manuals, Reference Values and Bibliography6.