Efficacy, Safety and Pharmacokinetics Study of Antroquinonol to Treat NSCLC

• Sponsor: Golden Biotechnology Corporation (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02047344
• Collaborator: ICON Clinical Research (Industry)
• Enrollment: 31
• Locations: 10
• Arm: 1
• Duration (Months): 62.2
• Patients Per Site: 3.1
• Patients Per Site Per Month: 0

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Non-small Cell Lung Cancer Stage IV	Drug: Antroquinonol	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 31 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official 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 NSCLC Who Have Failed Two Lines of Anti-Cancer Therapy
• Study Start Date: Oct 1, 2013
• Actual Primary Completion Date: Dec 7, 2018
• Actual Study Completion Date: Dec 7, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Antroquinonol (Hocena) 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.	Drug: Antroquinonol; 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.; Other Names: Hocena

Outcome Measures

Primary Outcome Measures

1. Progression Free Survival Rate [12 weeks]

   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 Outcome Measures

1. Cmax [8 hours]

   PK sampling will be performed on Days 0 and 28 in all patients enrolled in 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.

2. Disease Control Rate (DCR) [12 weeks]

   the proportion of patients with a documented CR, PR and SD during the first 12 week treatment cycle according to RECIST version 1.1.

3. T½: the Time Required for a Quantity to Reduce to Half Its Initial Value [8 hours]

   PK sampling will be performed on Days 0 and 28 in all patients enrolled in Stage 1.PK endpoints will be derived for intensively sampled PK profiles by T½: terminal half life

Other Outcome Measures

1. Objective Response Rate (ORR) [12 weeks]

   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.

2. Overall Survival [up to week 48]

   the time from the date of first administration of study drug to death from any cause

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Cytologically or histologically confirmed non squamous NSCLC Stage IV (including pleural effusion).

• Radiologically confirmed disease progression following two previous lines of anti-cancer therapy, one of which should be a platinum based regimen, OR the patient has refused treatment with approved treatment modalities

• At least one radiologically measurable target lesion per RECIST version 1.1

• Fresh or archival biopsy tissue available to determine tumor mutation status

• 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 mg/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)

• Recovery to Grade 1 or baseline of any toxicities due to prior treatments, excluding alopecia

Exclusion Criteria:

• 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 date of first administration of study drug

• Previous treatment with an histone deacetylase inhibitor or an epidermal growth factor receptor inhibitor within at least 4 weeks of the date of first administration of study drug

• Treatment with any drug(s) known to be an 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., Cohn'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)

• 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

• 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

• Pregnancy or breast feeding

• 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Arizona Clinical Research Center	Tucson	Arizona	United States	85715
2	UCSF	San Francisco	California	United States	94115
3	Rush University Medical Center	Chicago	Illinois	United States	60612
4	John Hopkins University	Baltimore	Maryland	United States	21287
5	Peninsula Regional Med Center	Salisbury	Maryland	United States	21801
6	Henry Ford health system	Detroit	Michigan	United States	48202
7	Guthrie Clinic, Ltd	Sayre	Pennsylvania	United States	18840
8	Chang Gung Memorial Hospital-Kaohsiung medical center	Kaohsiung		Taiwan	88301
9	National Cheng Kung University Hospitail	Tainan		Taiwan	704
10	Tri Service General Hospital	Taipei		Taiwan

Sponsors and Collaborators

• Golden Biotechnology Corporation
• ICON Clinical Research

Investigators

• Study Director: Howard Cheng, Ph.D., Golden Biotechnology Corp.

Study Documents (Full-Text)

• Study Protocol - Dec 6, 2017
• Statistical Analysis Plan - Aug 8, 2014

More Information

Publications

None provided.

• Responsible Party: Golden Biotechnology Corporation
• ClinicalTrials.gov Identifier: NCT02047344
• Other Study ID Numbers: GHNSCLC-2 001
• First Posted: Jan 28, 2014
• Last Update Posted: Dec 26, 2019
• Last Verified: Dec 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Golden Biotechnology Corporation: NSCLC
• Additional relevant MeSH terms: Carcinoma, Non-Small-Cell Lung

Study Results

Participant Flow

Recruitment Details	Unselected KRAS-positive and KRAS-negative patients with stage IV (including pleural effusion) non squamous NSCLC and 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.
Pre-assignment Detail	Written informed consent was obtained from all patients before initiating screening. The screening period was up to 42 days in duration (Days 42 to 1) for K-Ras testing result, if no history k-Ras result.

Arm/Group Title	K-Ras Negative	K- Ras Mutant
Arm/Group Description	Fresh or archival biopsy tissue to determine KRAS is not mutant.	Fresh or archival biopsy tissue to determine KRAS is mutant.
Period Title: Overall Study
STARTED	16	15
COMPLETED	16	15
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	K-Ras Negative	K- Ras Mutant	Total
Arm/Group Description	Fresh or archival biopsy tissue to determine KRAS is not mutant. Patients will receive one 12 week cycle of antroquinonol 200 mg t.i.d. or until disease progression.	Fresh or archival biopsy tissue to determine KRAS is mutant. Patients will receive one 12 week cycle of antroquinonol 200 mg t.i.d. or until disease progression.	Total of all reporting groups
Overall Participants	15	15	30
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	6 40%	3 20%	9 30%
>=65 years	9 60%	12 80%	21 70%
Sex: Female, Male (Count of Participants)
Female	4 26.7%	7 46.7%	11 36.7%
Male	11 73.3%	8 53.3%	19 63.3%
Race/Ethnicity, Customized (Count of Participants)
Asian	8 53.3%	1 6.7%	9 30%
Black or African American	1 6.7%	1 6.7%	2 6.7%
White	6 40%	13 86.7%	19 63.3%
Region of Enrollment (Count of Participants)
United States	7 46.7%	14 93.3%	21 70%
Taiwan	8 53.3%	1 6.7%	9 30%
ECOG performance status (Count of Participants)
Fully active	10 66.7%	1 6.7%	11 36.7%
Restricted in physically strenuous activity	4 26.7%	12 80%	16 53.3%
Capable of all selfcare more than 50% work	1 6.7%	2 13.3%	3 10%

Outcome Measures

1. Primary Outcome

Title	Progression Free Survival Rate
Description	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.
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

Defined as the proportion of patients alive and progression free at Week 12.

Arm/Group Title	Progression-free Survival Rate/KRAS Negative Group	Progression-free Survival Rate/KRAS Mutant Group
Arm/Group Description	200mg TID for treating KRAS negative patients 12 weeks	200mg TID for treating KRAS negative patients 12 weeks
Measure Participants	15	15
Count of Participants [Participants]	4 26.7%	0 0%

2. Secondary Outcome

Title	Cmax
Description	PK sampling will be performed on Days 0 and 28 in all patients enrolled in 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.
Time Frame	8 hours

Outcome Measure Data

Analysis Population Description

There were 22 patients with reported concentration data who were eligible for the PK population.

Arm/Group Title	Antroquinonol (Hocena)	Antroquinonol Day 28
Arm/Group Description	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.	continue use Antroquinonol for 28 Days
Measure Participants	22	22
Mean (Standard Deviation) [ng/mL]	276.87 (211.162)	393.55 (315.434)

3. Secondary Outcome

Title	Disease Control Rate (DCR)
Description	the proportion of patients with a documented CR, PR and SD during the first 12 week treatment cycle according to RECIST version 1.1.
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

26 patients can be run the full analysis

Arm/Group Title	Non- Prior Chemotherapies	One Line Failed Prior Chemotherapies	Two Lines Failed Prior Chemotherapies	More Than Two Lines Failed Prior Chemotherapies
Arm/Group Description	Patient without any chemotherapy before join Study	Patient join with One line failed prior chemotherapies	Patients join with two lines failed prior chemotherapies	patient failed more than two line chemotherapies before join.
Measure Participants	5	3	7	11
Number (95% Confidence Interval) [percentage of participants]	40 266.7%	0 0%	42.9 143%	72.7 NaN

4. Secondary Outcome

Title	T½: the Time Required for a Quantity to Reduce to Half Its Initial Value
Description	PK sampling will be performed on Days 0 and 28 in all patients enrolled in Stage 1.PK endpoints will be derived for intensively sampled PK profiles by T½: terminal half life
Time Frame	8 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Antroquinonol (Hocena)	Antroquinonol Day 28
Arm/Group Description	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.	continue use Antroquinonol for 28 Days
Measure Participants	22	22
Mean (Inter-Quartile Range) [hours]	3	2

5. Other Pre-specified Outcome

Title	Objective Response Rate (ORR)
Description	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.
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

full sey analysis group

Arm/Group Title	Antroquinonol (Hocena)
Arm/Group Description	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. Antroquinonol: 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.
Measure Participants	26
Number [patients]	0

6. Other Pre-specified Outcome

Title	Overall Survival
Description	the time from the date of first administration of study drug to death from any cause
Time Frame	up to week 48

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Non- Prior Chemotherapies	One Line Failed Prior Chemotherapies	Two Lines Failed Prior Chemotherapies	More Than Two Lines Failed Prior Chemotherapies
Arm/Group Description	Patient without any chemotherapy before join Study	Patient join with One line failed prior chemotherapies	Patients join with two lines failed prior chemotherapies	patient failed more than two line chemotherapies before join.
Measure Participants	5	3	7	11
week 12	60 400%	100 666.7%	100 333.3%	90.9 NaN
week 48	0 0%	100 666.7%	28.6 95.3%	39.3 NaN

Adverse Events

Time Frame	AEs collected for up to 48 weeks of the study from the time the patient signed the informed consent.
Adverse Event Reporting Description	Patients were followed for AEs from the date of informed consent until resolution or stabilization, alternative treatment for NSCLC was started 6 months after last dose of study drug, or loss to follow-up, whichever occurred first. In the event of serious or study drug-related toxicities, the patient was followed until resolution or stabilization. Safety follow up data was collected by telephone contact every 3 months after the EOS visit.
Arm/Group Title	Antroquinonol (Hocena)
Arm/Group Description	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.
All Cause Mortality
	Antroquinonol (Hocena)
	Affected / at Risk (%)	# Events
Total	14/31 (45.2%)
Serious Adverse Events
	Antroquinonol (Hocena)
	Affected / at Risk (%)	# Events
Total	12/31 (38.7%)
Cardiac disorders
Cardiac disorders	2/31 (6.5%)	3
Gastrointestinal disorders
Gastrointestinal disorders	2/31 (6.5%)	2
General disorders
General disorders and administration site conditions	2/31 (6.5%)	2
Infections and infestations
Infections and infestations	4/31 (12.9%)	4
Metabolism and nutrition disorders
Metabolism and nutrition disorders	2/31 (6.5%)	2
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)	3/31 (9.7%)	3
Nervous system disorders
Nervous system disorders	1/31 (3.2%)	1
Renal and urinary disorders
Renal and urinary disorders	2/31 (6.5%)	4
Respiratory, thoracic and mediastinal disorders
Respiratory, thoracic and mediastinal disorders	5/31 (16.1%)	5
Other (Not Including Serious) Adverse Events
	Antroquinonol (Hocena)
	Affected / at Risk (%)	# Events
Total	31/31 (100%)
Cardiac disorders
Tachycardia	2/31 (6.5%)	5
Gastrointestinal disorders
Gastrointestinal disorders	30/31 (96.8%)	30
General disorders
General disorders and administration site conditions	20/31 (64.5%)	20
Infections and infestations
Infections and infestations	6/31 (19.4%)	6
Investigations
Investigations	6/31 (19.4%)	6
Metabolism and nutrition disorders
Metabolism and nutrition disorders	11/31 (35.5%)	11
Musculoskeletal and connective tissue disorders
Musculoskeletal and connective tissue disorders	8/31 (25.8%)	8
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)	4/31 (12.9%)	4
Nervous system disorders
Nervous system disorders	11/31 (35.5%)	11
Psychiatric disorders
Psychiatric disorders	4/31 (12.9%)	4
Renal and urinary disorders
Renal and urinary disorders	4/31 (12.9%)	4
Respiratory, thoracic and mediastinal disorders
Respiratory, thoracic and mediastinal disorders	17/31 (54.8%)	17

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.