Trial Outcomes & Findings for Determine MTD and to Evaluate pk, Safety/Tolerability and Efficacy Profiles of Hocena® in NSCLC Subjects (NCT NCT01134016)

Results Overview

The study design consisted of 2 phases, the accelerated titration phase and the standard titration phase. During the accelerated titration phase, patients were enrolled in a cohort of 1 new patient for each dose level and treated for 4 weeks at that level. Any DLT or instance of MT during any 4 week treatment at any dose level led to the initiation of standard titration (3+3) phase. If none of the first 3 patients experienced any DLT, then dose escalation proceeded for the next cohort of patients. If 1 of 3 patients developed DLT, the cohort was expanded to at most 6 patients (another 3 patients added subsequently). If exactly 1 of the 6 patients experienced DLT, then escalation to the next dose level occurred. If more than 1 patient developed DLT in any dose cohort, the dose escalation was withheld and the prior dose level was considered as the MTD unless the present dose level was level 1

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

13 participants

Primary outcome timeframe

DLT is to be observed during 4 week period

Results posted on

2016-06-21

Participant Flow

A total of 13 patients were enrolled and treated: 1 patient each received 50, 100, 200, and 300 mg, 4 patients received 450 mg, and 5 patients received 600 mg. The recruitment period is from 19 Jan 2010 to 13 Dec 2012 in list two medical center, Taiwan.

This was an open-label, non-randomized, dose escalation, PK study to determine the MTD and DLTs and to explore the PK, safety/tolerability, and preliminary efficacy profiles of antroquinonol.

Participant milestones

Participant milestones
Measure	Antroquinonol Safety dose finding from 50mg to 600mg Antroquinonol : Dosage form: 50 mg and 100 mg capsules Dosage levels: 50 mg, 100 mg, 200 mg, 300mg, 450mg and 600mg ( 6 cohorts) Frequency: take daily for 4 weeks per subject per dosage level
Overall Study STARTED	13
Overall Study COMPLETED	10
Overall Study NOT COMPLETED	3

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Determine MTD and to Evaluate pk, Safety/Tolerability and Efficacy Profiles of Hocena® in NSCLC Subjects

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Antroquinonol n=13 Participants Safety dose finding from 50mg to 600mg Antroquinonol : Dosage form: 50 mg and 100 mg capsules Dosage levels: 50 mg, 100 mg, 200 mg, 300mg, 450mg and 600mg ( 6 cohorts) Frequency: take daily for 4 weeks per subject per dosage level
Age, Categorical <=18 years	0 Participants n=93 Participants
Age, Categorical Between 18 and 65 years	7 Participants n=93 Participants
Age, Categorical >=65 years	6 Participants n=93 Participants
Sex: Female, Male Female	6 Participants n=93 Participants
Sex: Female, Male Male	7 Participants n=93 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=93 Participants
Race (NIH/OMB) Asian	13 Participants n=93 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=93 Participants
Race (NIH/OMB) Black or African American	0 Participants n=93 Participants
Race (NIH/OMB) White	0 Participants n=93 Participants
Race (NIH/OMB) More than one race	0 Participants n=93 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=93 Participants
Region of Enrollment Taiwan	13 participants n=93 Participants
Height	159.76 cm n=93 Participants
Weight	64.57 Kg n=93 Participants
BMI	25.214 kg/m^2 n=93 Participants

PRIMARY outcome

Timeframe: DLT is to be observed during 4 week period

Population: Intent-to-Treat (ITT) Population: All patients who received at least 1 dose of antroquinonol.

The study design consisted of 2 phases, the accelerated titration phase and the standard titration phase. During the accelerated titration phase, patients were enrolled in a cohort of 1 new patient for each dose level and treated for 4 weeks at that level. Any DLT or instance of MT during any 4 week treatment at any dose level led to the initiation of standard titration (3+3) phase. If none of the first 3 patients experienced any DLT, then dose escalation proceeded for the next cohort of patients. If 1 of 3 patients developed DLT, the cohort was expanded to at most 6 patients (another 3 patients added subsequently). If exactly 1 of the 6 patients experienced DLT, then escalation to the next dose level occurred. If more than 1 patient developed DLT in any dose cohort, the dose escalation was withheld and the prior dose level was considered as the MTD unless the present dose level was level 1

Outcome measures

Outcome measures
Measure	Antroquinonol n=13 Participants Maximum Tolerable Dose for Antroquinonol	Tmax Day 1: 100 mg Patient represent the time to reach the maximum plasma concentration after dose	Tmax Day 1: 200mg Patient represent the time to reach the maximum plasma concentration after dose	Tmax Day 1: 300mg Patient represent the time to reach the maximum plasma concentration after dose	Tmax Day 1: 450mg Patient represent the time to reach the maximum plasma concentration after dose	Tmax Day 1 :600 mg Patient represent the time to reach the maximum plasma concentration after dose	Tmax Day 28: 50mg Patient represent the time to reach the maximum plasma concentration after dose	Tmax Day 28: 100mg Patient represent the time to reach the maximum plasma concentration after dose	Tmax Day 28: 200 mg Patient represent the time to reach the maximum plasma concentration after dose	Tmax Day 28: 300mg Patient represent the time to reach the maximum plasma concentration after dose	Tmax Day 28: 450mg Patient represent the time to reach the maximum plasma concentration after dose	Tmax Day 28: 600mg Patient represent the time to reach the maximum plasma concentration after dose
To Determind the Maximum Tolerable Dose for Antroquinonol	600 mg	—	—	—	—	—	—	—	—	—	—	—

SECONDARY outcome

Timeframe: 30 minutes prior to and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10, 14, and 24 hours after dose of Day 1&28

Pharmacokinetic samples will be obtained from all the patients in each dose cohort treated in all phases of the study. Patients will only be sampled during their first treatment cycle only. Individual serum concentration versus (vs) time curves were plotted in 1 graph by dose level on both linear/linear and log10/linear scales. Mean serum concentration vs time curves were also presented in 1 graph for dose levels on both linear/linear and log10/linear scales.

Outcome measures

Outcome measures
Measure	Antroquinonol n=1 Participants Maximum Tolerable Dose for Antroquinonol	Tmax Day 1: 100 mg n=1 Participants Patient represent the time to reach the maximum plasma concentration after dose	Tmax Day 1: 200mg n=1 Participants Patient represent the time to reach the maximum plasma concentration after dose	Tmax Day 1: 300mg n=1 Participants Patient represent the time to reach the maximum plasma concentration after dose	Tmax Day 1: 450mg n=4 Participants Patient represent the time to reach the maximum plasma concentration after dose	Tmax Day 1 :600 mg n=5 Participants Patient represent the time to reach the maximum plasma concentration after dose	Tmax Day 28: 50mg n=1 Participants Patient represent the time to reach the maximum plasma concentration after dose	Tmax Day 28: 100mg n=1 Participants Patient represent the time to reach the maximum plasma concentration after dose	Tmax Day 28: 200 mg n=1 Participants Patient represent the time to reach the maximum plasma concentration after dose	Tmax Day 28: 300mg n=1 Participants Patient represent the time to reach the maximum plasma concentration after dose	Tmax Day 28: 450mg n=3 Participants Patient represent the time to reach the maximum plasma concentration after dose	Tmax Day 28: 600mg n=3 Participants Patient represent the time to reach the maximum plasma concentration after dose
Tmax After Dose	2.00 hours Interval 2.0 to 2.0	1.00 hours Interval 1.0 to 1.0	10.00 hours Interval 10.0 to 10.0	1.13 hours Interval 1.13 to 1.13	1.82 hours Interval 1.08 to 3.97	3.70 hours Interval 2.0 to 9.7	1.92 hours Interval 1.92 to 1.92	3.17 hours Interval 3.17 to 3.17	4.00 hours Interval 4.0 to 4.0	4.05 hours Interval 4.05 to 4.05	3.00 hours Interval 1.07 to 6.2	3.15 hours Interval 2.07 to 3.87

SECONDARY outcome

Timeframe: 30 minutes prior to and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10, 14, and 24 hours after dose of Day 1&28

Pharmacokinetic samples will be obtained from all the patients in each dose cohort treated in all phases of the study. Patients will only be sampled during their first treatment cycle only. Individual serum concentration versus (vs) time curves were plotted in 1 graph by dose level on both linear/linear and log10/linear scales. Mean serum concentration vs time curves were also presented in 1 graph for dose levels on both linear/linear and log10/linear scales.

Outcome measures

Outcome measures
Measure	Antroquinonol n=1 Participants Maximum Tolerable Dose for Antroquinonol	Tmax Day 1: 100 mg n=1 Participants Patient represent the time to reach the maximum plasma concentration after dose	Tmax Day 1: 200mg n=1 Participants Patient represent the time to reach the maximum plasma concentration after dose	Tmax Day 1: 300mg n=1 Participants Patient represent the time to reach the maximum plasma concentration after dose	Tmax Day 1: 450mg n=4 Participants Patient represent the time to reach the maximum plasma concentration after dose	Tmax Day 1 :600 mg n=5 Participants Patient represent the time to reach the maximum plasma concentration after dose	Tmax Day 28: 50mg n=1 Participants Patient represent the time to reach the maximum plasma concentration after dose	Tmax Day 28: 100mg n=1 Participants Patient represent the time to reach the maximum plasma concentration after dose	Tmax Day 28: 200 mg n=1 Participants Patient represent the time to reach the maximum plasma concentration after dose	Tmax Day 28: 300mg n=1 Participants Patient represent the time to reach the maximum plasma concentration after dose	Tmax Day 28: 450mg n=3 Participants Patient represent the time to reach the maximum plasma concentration after dose	Tmax Day 28: 600mg n=3 Participants Patient represent the time to reach the maximum plasma concentration after dose
Half-life Time From Overall Study	2.42 hours	1.30 hours	4.33 hours	1.93 hours	2.38 hours Standard Deviation 1.34	3.07 hours Standard Deviation 1.52	1.60 hours	2.34 hours	1.41 hours	2.11 hours	1.81 hours Standard Deviation 0.66	2.55 hours Standard Deviation 1.30

SECONDARY outcome

Timeframe: 30 minutes prior to and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10, 14, and 24 hours after dose of Day 1

Population: Pharmacokinetic (PK) Population: All patients who received at least 1 dose of antroquinonol with sufficient post-dose bio-samples collected for PK profile characterization.

Pharmacokinetic samples will be obtained from all the patients in each dose cohort treated in all phases of the study. Patients will only be sampled during their first treatment cycle only.

Outcome measures

Outcome measures
Measure	Antroquinonol n=13 Participants Maximum Tolerable Dose for Antroquinonol	Tmax Day 1: 100 mg Patient represent the time to reach the maximum plasma concentration after dose	Tmax Day 1: 200mg Patient represent the time to reach the maximum plasma concentration after dose	Tmax Day 1: 300mg Patient represent the time to reach the maximum plasma concentration after dose	Tmax Day 1: 450mg Patient represent the time to reach the maximum plasma concentration after dose	Tmax Day 1 :600 mg Patient represent the time to reach the maximum plasma concentration after dose	Tmax Day 28: 50mg Patient represent the time to reach the maximum plasma concentration after dose	Tmax Day 28: 100mg Patient represent the time to reach the maximum plasma concentration after dose	Tmax Day 28: 200 mg Patient represent the time to reach the maximum plasma concentration after dose	Tmax Day 28: 300mg Patient represent the time to reach the maximum plasma concentration after dose	Tmax Day 28: 450mg Patient represent the time to reach the maximum plasma concentration after dose	Tmax Day 28: 600mg Patient represent the time to reach the maximum plasma concentration after dose
Maximum Plasma Concentration After on Day 1	0.504 Log(mg/ml) Interval 0.17 to 0.83	—	—	—	—	—	—	—	—	—	—	—

SECONDARY outcome

Timeframe: 30 minutes prior to and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10, 14, and 24 hours after dose of Day 28

Pharmacokinetic samples will be obtained from all the patients in each dose cohort treated in all phases of the study. Patients will only be sampled during their first treatment cycle only.

Outcome measures

Outcome measures
Measure	Antroquinonol n=10 Participants Maximum Tolerable Dose for Antroquinonol	Tmax Day 1: 100 mg Patient represent the time to reach the maximum plasma concentration after dose	Tmax Day 1: 200mg Patient represent the time to reach the maximum plasma concentration after dose	Tmax Day 1: 300mg Patient represent the time to reach the maximum plasma concentration after dose	Tmax Day 1: 450mg Patient represent the time to reach the maximum plasma concentration after dose	Tmax Day 1 :600 mg Patient represent the time to reach the maximum plasma concentration after dose	Tmax Day 28: 50mg Patient represent the time to reach the maximum plasma concentration after dose	Tmax Day 28: 100mg Patient represent the time to reach the maximum plasma concentration after dose	Tmax Day 28: 200 mg Patient represent the time to reach the maximum plasma concentration after dose	Tmax Day 28: 300mg Patient represent the time to reach the maximum plasma concentration after dose	Tmax Day 28: 450mg Patient represent the time to reach the maximum plasma concentration after dose	Tmax Day 28: 600mg Patient represent the time to reach the maximum plasma concentration after dose
Maximum Plasma Concentration After Dosing on Day 28	0.682 log(mg/ml) Interval 0.08 to 1.28	—	—	—	—	—	—	—	—	—	—	—

SECONDARY outcome

Timeframe: within 30 minutes prior to and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10, 14, and 24 hours after dose of Day 1

Pharmacokinetic samples will be obtained from all the patients in each dose cohort treated in all phases of the study. Patients will only be sampled during their first treatment cycle only.

Outcome measures

Outcome measures
Measure	Antroquinonol n=13 Participants Maximum Tolerable Dose for Antroquinonol	Tmax Day 1: 100 mg Patient represent the time to reach the maximum plasma concentration after dose	Tmax Day 1: 200mg Patient represent the time to reach the maximum plasma concentration after dose	Tmax Day 1: 300mg Patient represent the time to reach the maximum plasma concentration after dose	Tmax Day 1: 450mg Patient represent the time to reach the maximum plasma concentration after dose	Tmax Day 1 :600 mg Patient represent the time to reach the maximum plasma concentration after dose	Tmax Day 28: 50mg Patient represent the time to reach the maximum plasma concentration after dose	Tmax Day 28: 100mg Patient represent the time to reach the maximum plasma concentration after dose	Tmax Day 28: 200 mg Patient represent the time to reach the maximum plasma concentration after dose	Tmax Day 28: 300mg Patient represent the time to reach the maximum plasma concentration after dose	Tmax Day 28: 450mg Patient represent the time to reach the maximum plasma concentration after dose	Tmax Day 28: 600mg Patient represent the time to reach the maximum plasma concentration after dose
AUC0-t on Day 1	0.641 log(mg*hr/mL) Interval 0.16 to 1.12	—	—	—	—	—	—	—	—	—	—	—

SECONDARY outcome

Timeframe: 30 minutes prior to and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10, 14, and 24 hours after dose of Day 28

Pharmacokinetic samples will be obtained from all the patients in each dose cohort treated in all phases of the study. Patients will only be sampled during their first treatment cycle only.

Outcome measures

Outcome measures
Measure	Antroquinonol n=10 Participants Maximum Tolerable Dose for Antroquinonol	Tmax Day 1: 100 mg Patient represent the time to reach the maximum plasma concentration after dose	Tmax Day 1: 200mg Patient represent the time to reach the maximum plasma concentration after dose	Tmax Day 1: 300mg Patient represent the time to reach the maximum plasma concentration after dose	Tmax Day 1: 450mg Patient represent the time to reach the maximum plasma concentration after dose	Tmax Day 1 :600 mg Patient represent the time to reach the maximum plasma concentration after dose	Tmax Day 28: 50mg Patient represent the time to reach the maximum plasma concentration after dose	Tmax Day 28: 100mg Patient represent the time to reach the maximum plasma concentration after dose	Tmax Day 28: 200 mg Patient represent the time to reach the maximum plasma concentration after dose	Tmax Day 28: 300mg Patient represent the time to reach the maximum plasma concentration after dose	Tmax Day 28: 450mg Patient represent the time to reach the maximum plasma concentration after dose	Tmax Day 28: 600mg Patient represent the time to reach the maximum plasma concentration after dose
AUC0-t on Day 28	0.957 log(mg*hr/mL) Interval 0.59 to 1.32	—	—	—	—	—	—	—	—	—	—	—

SECONDARY outcome

Timeframe: pre-screening and end of treatment

Population: Per-protocol (PP) Population: All patients who completed at least 3 cycles of treatment with proper imaging assessment (RECIST).

Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for overall response by CT: Judgement by total siutation of target, non-target and new lesions. Meaning of Target lesion: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), Sum down 30% or more from target lesion baseline; Progressive Disease(PD), Sum up at least 20% from smallest value (nadir) and Absolute increase ≥ 5 mm; Stable Disease (SD), Neither enough shrinkage for PR nor enough growth for PD. non-target lesion: CR: All non-target lesions disappeared and All lymph nodes \<10 mm; Non-CR/Non-PD: Non-target lesion(s) still present and Lymph nodes ≥10 mm; PD: Unequivocal progression; New lesion :Unequivocal new cancer lesions Overall SD response should be better than SD at target lesion, better than Non-CR/Non-PD t non-target lesion and no new lesion.

Outcome measures

Outcome measures
Measure	Antroquinonol n=3 Participants Maximum Tolerable Dose for Antroquinonol	Tmax Day 1: 100 mg Patient represent the time to reach the maximum plasma concentration after dose	Tmax Day 1: 200mg Patient represent the time to reach the maximum plasma concentration after dose	Tmax Day 1: 300mg Patient represent the time to reach the maximum plasma concentration after dose	Tmax Day 1: 450mg Patient represent the time to reach the maximum plasma concentration after dose	Tmax Day 1 :600 mg Patient represent the time to reach the maximum plasma concentration after dose	Tmax Day 28: 50mg Patient represent the time to reach the maximum plasma concentration after dose	Tmax Day 28: 100mg Patient represent the time to reach the maximum plasma concentration after dose	Tmax Day 28: 200 mg Patient represent the time to reach the maximum plasma concentration after dose	Tmax Day 28: 300mg Patient represent the time to reach the maximum plasma concentration after dose	Tmax Day 28: 450mg Patient represent the time to reach the maximum plasma concentration after dose	Tmax Day 28: 600mg Patient represent the time to reach the maximum plasma concentration after dose
Number of Participants in the PP Population With Better Than SD at Target Lesion, Better Than Non-CR/Non-PD at Non-target Lesion and no New Lesion	3 participants	—	—	—	—	—	—	—	—	—	—	—

SECONDARY outcome

Timeframe: pre-screenting and every 14-day period

1. Hematology laboratory data 2. Biochemistry laboratory data 3. Urinalysis 4. AE; AE not including the natural progress of the underlying disease 5. Incidence of toxicity ≥ grade 3 according to NCI CTCAE version 4.03 6. Physical examination 7. Vital signs changes 8. Electrocardiogram examination results (including HR, QRS, QT, QTc, RR intervals)

Outcome measures

Outcome data not reported

Adverse Events

Antroquinonol

Serious events: 0 serious events

Other events: 13 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Other adverse events
Measure	Antroquinonol n=13 participants at risk Safety dose finding from 50mg to 600mg Antroquinonol : Dosage form: 50 mg and 100 mg capsules Dosage levels: 50 mg, 100 mg, 200 mg, 300mg, 450mg and 600mg ( 6 cohorts) Frequency: take daily for 4 weeks per subject per dosage level
Gastrointestinal disorders diarrhea	92.3% 12/13 • Number of events 12 • recorded immediatly as AE happen treatment-emergent adverse events (TEAEs) were reported as determined by the NCI CTCAE, Version 4.03. reported only related to the study drug
Gastrointestinal disorders vomiting	69.2% 9/13 • Number of events 9 • recorded immediatly as AE happen treatment-emergent adverse events (TEAEs) were reported as determined by the NCI CTCAE, Version 4.03. reported only related to the study drug
Gastrointestinal disorders nausea	53.8% 7/13 • Number of events 7 • recorded immediatly as AE happen treatment-emergent adverse events (TEAEs) were reported as determined by the NCI CTCAE, Version 4.03. reported only related to the study drug

Additional Information

Dr. Howard Cheng, Director of clinical trials

Golden Biotechnology Corp.

Phone: 886-2808-6006

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee All the PI should grand sponcer's agree to discuss or publish trial results after the trial is completed.
Publication restrictions are in place

Restriction type: OTHER