Non-small Cell Lung Cancer
Conditions
Keywords
Lung cancer, NSCLC
Brief summary
A phase I study to determine the maximum tolerable dose (MTD) and to evaluate pharmacokinetic, safety/tolerability and efficacy profiles of antroquinonol (Hocena®) in non-small cell lung cancer (NSCLC) subjects refractory to conventional treatment modalities
Detailed description
1. Antroquinonol, a novel cyclohexenone compound, is a purified compound from extract of Antrodia camphorata. 2. The pharmacological effects of antroquinonol were postulated to exert its antitumorigenesis effects through interactions to primary targets of epidermal growth factor receptor (EGFR)/Akt/mitogen-activated protein kinase (MAPK). 3. In vivo study in NOD/SCID mice with A549 subcutaneous xenografts consistently showed tumor growth suppression after 2 weeks of oral 30 and 60 mg/kg antroquinonol treatment.
Interventions
DRUGAntroquinonol
Antroquinonol was taken orally, daily, within 15 minutes after a breakfast at the assigned dose level: 50, 100, 200, 300, 450, 600 mg/day for 4 weeks. Dose Level 1 (4 weeks) : 50 mg Antroquinonol; Dose Level 2 (4 weeks) : 100mg Antroquinonol; Dose Level 3 (4 weeks) : 200mg Antroquinonol; Dose Level 4 (4 weeks) : 300mg Antroquinonol; Dose Level 5 (4 weeks) : 450mg Antroquinonol; Dose Level 6 (4 weeks) : 600mg Antroquinonol. The accelerated phase ended when either 1 DLT or MT was observed to start standard phase. Study ended when reach the highest dose level or DLT founded.
Sponsors
PharmaNet
Golden Biotechnology Corporation
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Age ≥ 20 years. 2. Diagnosed stage III/IV NSCLC. The grading is determined according to the Tumor-Node-Metastasis (TNM) staging system for lung cancer. 3. Patients with histologically or cytologically proven primary NSCLC with adenocarcinoma or mixed cell type with adenocarcinoma, who have failed on standard treatments. 4. With progressive tumor after two lines of chemotherapy (including one platinum-based) and 1 EGFR-targeted therapy if patient is identified with EGFR mutation or his/her EGFR mutation status is unknown OR having refused further currently approved treatment modalities. 5. Life expectancy ≥ 3 months. 6. Within 1 week of planned first study treatment day, adequate hematopoietic functions are presented: Total white blood cell (WBC) ≥ 3500 cells/mm3 Hemoglobin (Hb) ≥ 9.0 g/dL Platelets ≥ 100,000 cells/mm3 Absolute neutrophil count (ANC) ≥ 1500 /mm3 7. Within 1 week of planned first study treatment day, adequate hepatic and renal functions are presented: Total bilirubin ≤2.0 mg/dLGOLANTA20090911, Amendment 4/v. 1.0/ 13 October 2010 AST ≤ 3 × upper limit of normal (ULN); patients with liver metastasis: AST ≤ 5 × ULN ALT ≤ 3 × ULN; patients with liver metastasis: ALT ≤ 5 × ULN Creatinine ≤ 1.5 mg/dL 8. Must have recovered from toxicities of previous anti-cancer treatments to grade 1 NCI-CTC or better, except for alopecia. 9. Eastern Cooperative Oncology Group (ECOG) performance score ≤ 2. 10. Female patient with childbearing potential confirmed of not being pregnant at the screening; and informed that effective contraception must be used during the entire treatment period of this study and for 6 months after exiting from the study. 11. Given signed and dated written informed consent form.
Exclusion criteria
1. Primary major surgery \< 4 weeks prior to the planned first study treatment day. 2. Lactating, pregnant or plans to be become pregnant. 3. Except for alopecia, recovered from any previous treatments to a grade 1 or less prior to the planned first study treatment day. 4. With active systemic infections, active and clinically significant cardiac diseases, active gastrointestinal ulcers, or medical conditions that may significantly affect adequate absorption of investigational product. 5. Within 5 years, prior history of malignancy other than NSCLC, except cervical carcinoma in situ and basal or squamous cell skin carcinoma. 6. Known allergic to antroquinonol or its formulation excipients. 7. Within 14 days of planned first study treatment day, exposed to any drug(s) known to be significant CYP2C19, 3A4, 2C8, and 2E1, inhibitor or activator. 8. With conditions judged by the investigator as unsuitable for the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| To Determind the Maximum Tolerable Dose for Antroquinonol | DLT is to be observed during 4 week period | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Half-life Time From Overall Study | 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. |
| Maximum Plasma Concentration After on Day 1 | 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. |
| Maximum Plasma Concentration After Dosing on Day 28 | 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. |
| Tmax After Dose | 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. |
| AUC0-t on Day 28 | 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. |
| 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 | pre-screening and end of treatment | 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. |
| Safety Blood and Urine Test | 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) |
| AUC0-t on Day 1 | 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. |
Countries
Taiwan
Participant flow
Recruitment details
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.
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| 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 | 13 |
| Total | 13 |
Baseline characteristics
| Characteristic | Antroquinonol |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 6 Participants |
| Age, Categorical Between 18 and 65 years | 7 Participants |
| BMI | 25.214 kg/m^2 |
| Height | 159.76 cm |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 13 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 0 Participants |
| Region of Enrollment Taiwan | 13 participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 7 Participants |
| Weight | 64.57 Kg |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 13 / 13 |
| serious Total, serious adverse events | 0 / 13 |
Outcome results
Primary
To Determind the Maximum Tolerable Dose for 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
Time frame: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Antroquinonol | To Determind the Maximum Tolerable Dose for Antroquinonol | 600 mg |
Secondary
AUC0-t on 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.
Time frame: 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
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Antroquinonol | AUC0-t on Day 1 | 0.641 log(mg*hr/mL) |
Secondary
AUC0-t on 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.
Time frame: 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
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Antroquinonol | AUC0-t on Day 28 | 0.957 log(mg*hr/mL) |
Secondary
Half-life Time From Overall Study
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.
Time frame: 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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Antroquinonol | Half-life Time From Overall Study | 2.42 hours | — |
| Tmax Day 1: 100 mg | Half-life Time From Overall Study | 1.30 hours | — |
| Tmax Day 1: 200mg | Half-life Time From Overall Study | 4.33 hours | — |
| Tmax Day 1: 300mg | Half-life Time From Overall Study | 1.93 hours | — |
| Tmax Day 1: 450mg | Half-life Time From Overall Study | 2.38 hours | Standard Deviation 1.34 |
| Tmax Day 1 :600 mg | Half-life Time From Overall Study | 3.07 hours | Standard Deviation 1.52 |
| Tmax Day 28: 50mg | Half-life Time From Overall Study | 1.60 hours | — |
| Tmax Day 28: 100mg | Half-life Time From Overall Study | 2.34 hours | — |
| Tmax Day 28: 200 mg | Half-life Time From Overall Study | 1.41 hours | — |
| Tmax Day 28: 300mg | Half-life Time From Overall Study | 2.11 hours | — |
| Tmax Day 28: 450mg | Half-life Time From Overall Study | 1.81 hours | Standard Deviation 0.66 |
| Tmax Day 28: 600mg | Half-life Time From Overall Study | 2.55 hours | Standard Deviation 1.3 |
Secondary
Maximum Plasma Concentration After Dosing on 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.
Time frame: 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
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Antroquinonol | Maximum Plasma Concentration After Dosing on Day 28 | 0.682 log(mg/ml) |
Secondary
Maximum Plasma Concentration After on 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.
Time frame: 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.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Antroquinonol | Maximum Plasma Concentration After on Day 1 | 0.504 Log(mg/ml) |
Secondary
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
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.
Time frame: 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).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Antroquinonol | 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
Safety Blood and Urine Test
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)
Time frame: pre-screenting and every 14-day period
Secondary
Tmax After Dose
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.
Time frame: 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
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Antroquinonol | Tmax After Dose | 2.00 hours |
| Tmax Day 1: 100 mg | Tmax After Dose | 1.00 hours |
| Tmax Day 1: 200mg | Tmax After Dose | 10.00 hours |
| Tmax Day 1: 300mg | Tmax After Dose | 1.13 hours |
| Tmax Day 1: 450mg | Tmax After Dose | 1.82 hours |
| Tmax Day 1 :600 mg | Tmax After Dose | 3.70 hours |
| Tmax Day 28: 50mg | Tmax After Dose | 1.92 hours |
| Tmax Day 28: 100mg | Tmax After Dose | 3.17 hours |
| Tmax Day 28: 200 mg | Tmax After Dose | 4.00 hours |
| Tmax Day 28: 300mg | Tmax After Dose | 4.05 hours |
| Tmax Day 28: 450mg | Tmax After Dose | 3.00 hours |
| Tmax Day 28: 600mg | Tmax After Dose | 3.15 hours |