Neoplasm
Conditions
Keywords
VGEF inhibitor, Anti angiogenesis, Advanced Solid Tumors
Brief summary
This study will test a new cancer medication to determine if this medication will block blood supply to a tumor and decrease growth of a tumor. This study will also define the safety profile and define the safest dose of this new medication for people who have cancer.
Interventions
DRUGPF-00337210
0.67mg Capsule Once Daily (Accelerated Dose Escalation) Continuous
Sponsors
University of Wisconsin, Madison
Pfizer
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically or cytologically confirmed advanced solid tumors un-responsive to currently available therapies or for which there is no standard therapy. * At least 1 measurable disease site as defined by Response Evaluation Criterion in Solid Tumors \[RECIST\]. * Adequate bone marrow, liver function and renal function as defined by protocol. * Blood pressure Requirements During dose escalation - no evidence of pre-existing hypertension and no antihypertensive medications at baseline. During dose expansion - patient's whose hypertension is controlled by antihypertensive therapy.
Exclusion criteria
* Chemotherapy, radiotherapy or any investigational therapy within 4 weeks of study entry * Current use or anticipated need for drugs that are known CYP34 inhibitors or inducers. * Patients with carcinomatous meningitis or un-treated brain metastases. * Any acute cardiovascular incident within the past 12 months. * Patients with active gastrointestinal bleeding or significant gastrointestinal abnormalities as defined by protocol * Patients with no evidence of the following for 5 years: malignancy or metastatic disease of skin cancer (except melanoma), in situ cervical cancer or breast cancer or T1C prostate cancer.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Recommended Phase-2 Dose (RP2D) | Day 28 | RP2D was determined based on the safety profile and pharmacodynamic findings. The twice daily dosing was preferred over once daily dosing for RP2D, as per investigator's discretion, due to more consistent changes in pharmacodynamic markers and greater clinical benefit observed in twice daily dosing. |
| Number of Participants With Dose-limiting Toxicities (DLTs) | Baseline up to Day 28 | DLTs included events occurring in Cycle 1: blood pressure of 180/110 millimeters of mercury (mmHg) or higher for 3 readings over 3 hours regardless of use of anti-hypertensive drugs or greater than (\>) 160/100 mmHg for 3 readings over 3 days on maximum anti-hypertensive drugs; afebrile Grade 4 neutropenia for greater than or equal to (\>=) 7 days or \>=Grade 3 neutropenia associated with fever (1 reading of oral temperature \>38.5 degree Celsius \[degree C\] or 3 readings of oral temperature \>38.0 degree C in 24-hour period); Grade 4 thrombocytopenia; hemoptysis of \>1/2 teaspoon of bright red blood per day; proteinuria of \>=2 grams/24 hours; inability to resume PF-00337210 dosing at current dose level within 14 days of stopping due to treatment-related toxicity; \>=Grade 3 nonhematological toxicities (except alopecia and blood pressure/hypertension); Grade 3 nonhematological toxicities that could be controlled to Grade 2 or less with appropriate treatment were not considered dose limiting. |
| Maximum Tolerated Dose (MTD) | Day 28 | MTD: dose level at which no more than 1 of 6 participants experienced DLT during Cycle 1. DLTs: blood pressure of 180/110 mmHg or higher for 3 readings over 3 hours regardless of use of anti-hypertensive drugs or \>160/100 mmHg for 3 readings over 3 days on maximum anti-hypertensive drugs; afebrile Grade 4 neutropenia \>=7 days or \>= Grade 3 neutropenia associated with fever (1 reading of oral temperature \>38.5 degree C or 3 readings of oral temperature \>38.0 degree C in 24-hour period); Grade 4 thrombocytopenia; hemoptysis of \>1/2 teaspoon of bright red blood per day; proteinuria of \>=2 grams/24 hours; inability to resume PF-00337210 dosing at current dose level within 14 days of stopping due to treatment-related toxicity; \>=Grade 3 nonhematological toxicities (except alopecia and blood pressure/hypertension); Grade 3 nonhematological toxicities that could be controlled to Grade 2 or less with appropriate treatment were not considered dose limiting. |
| Maximum Administered Dose (MAD) | Day 28 | MAD: dose level at which 2 or more out of 6 participants experienced DLT during Cycle 1. DLTs: blood pressure of 180/110 mmHg or higher for 3 readings over 3 hours regardless of use of anti-hypertensive drugs or \>160/100 mmHg for 3 readings over 3 days on maximum anti-hypertensive drugs; afebrile Grade 4 neutropenia \>=7 days or \>= Grade 3 neutropenia associated with fever (1 reading of oral temperature \>38.5 degree C or 3 readings of oral temperature \>38.0 degree C in 24-hour period); Grade 4 thrombocytopenia; hemoptysis of \>1/2 teaspoon of bright red blood per day; proteinuria of \>=2 grams/24 hours; inability to resume PF-00337210 dosing at current dose level within 14 days of stopping due to treatment-related toxicity; \>=Grade 3 nonhematological toxicities (except alopecia and blood pressure/hypertension); Grade 3 nonhematological toxicities that could be controlled to Grade 2 or less with appropriate treatment were not considered dose limiting. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] | Pre-dose,0.5,1,2,4,6,8,10,16,20,24 hrs post-dose on Day 1(0.67 mg group);pre-dose,0.5,1,2,4,6,8,18,20,24 hrs post-dose on Day 1,15,29(once daily groups);pre-dose,0.5,1,2,4,6,8 hrs post-dose on Day 1,15,29 (twice daily groups);pre-dose on Day 43, 57 | AUC (0 - ∞)= Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - ∞). It is obtained from AUC (0 - t) plus AUC (t - ∞). |
| Apparent Volume of Distribution (Vss) | Pre-dose,0.5,1,2,4,6,8,10,16,20,24 hrs post-dose on Day 1(0.67 mg group);pre-dose,0.5,1,2,4,6,8,18,20,24 hrs post-dose on Day 1,15,29(once daily groups);pre-dose,0.5,1,2,4,6,8 hrs post-dose on Day 1,15,29 (twice daily groups);pre-dose on Day 43, 57 | Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose is influenced by the fraction absorbed. |
| Number of Participants With Objective Response of Complete Response or Partial Response | Baseline, every 8 weeks up to Cycle 25 (Week 100) | Number of participants with objective response based on assessment of confirmed complete response (CR) or confirmed partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST). Confirmed CR defined as disappearance of all target and non-target lesions and no appearance of new lesions. Confirmed PR defined as at least 30 percent decrease in sum of the longest dimensions (LD) of the target lesions, taking as a reference the baseline sum LD, without progression of non-target lesions and no appearance of new lesions. Confirmed responses are those that persist on repeat imaging study \>=4 weeks after initial documentation of response. |
| Change From Baseline in Biomarkers at Day 1 of Each Cycle up to Cycle 25 | Baseline, Day 1 of Cycle 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 | Biomarkers included soluble plasma proteins associated with angiogenesis (vascular endothelial growth factor \[VEGF\], soluble vascular endothelial growth factor-2 receptor \[sVEGFR2\], soluble vascular endothelial growth factor-3 receptor \[sVEGFR3\], soluble beta type platelet-derived growth factor \[sPDGFR beta\]) and tumor proliferation (soluble stem-cell factor receptor \[sKIT\]) |
| Systemic Clearance (CL) | Pre-dose,0.5,1,2,4,6,8,10,16,20,24 hrs post-dose on Day 1(0.67 mg group);pre-dose,0.5,1,2,4,6,8,18,20,24 hrs post-dose on Day 1,15,29(once daily groups);pre-dose,0.5,1,2,4,6,8 hrs post-dose on Day 1,15,29 (twice daily groups);pre-dose on Day 43, 57 | CL is a quantitative measure of the rate at which a drug substance is removed from the body. |
| Maximum Observed Plasma Concentration (Cmax) | Pre-dose,0.5,1,2,4,6,8,10,16,20,24 hours(hrs) post-dose on Day 1(0.67 mg group);pre-dose,0.5,1,2,4,6,8,18,20,24 hrs post-dose on Day 1,15,29(once daily groups);pre-dose,0.5,1,2,4,6,8 hrs post-dose on Day 1,15,29 (twice daily groups);pre-dose on Day 43, 57 | — |
| Plasma Decay Half-Life (t1/2) | Pre-dose,0.5,1,2,4,6,8,10,16,20,24 hrs post-dose on Day 1(0.67 mg group);pre-dose,0.5,1,2,4,6,8,18,20,24 hrs post-dose on Day 1,15,29(once daily groups);pre-dose,0.5,1,2,4,6,8 hrs post-dose on Day 1,15,29 (twice daily groups);pre-dose on Day 43, 57 | Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. |
| Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC (0-24)] | Pre-dose,0.5,1,2,4,6,8,10,16,20,24 hrs post-dose on Day 1(0.67 mg group);pre-dose,0.5,1,2,4,6,8,18,20,24 hrs post-dose on Day 1,15,29(once daily groups);pre-dose,0.5,1,2,4,6,8 hrs post-dose on Day 1,15,29 (twice daily groups);pre-dose on Day 43, 57 | AUC (0-24)= Area under the plasma concentration versus time curve from time zero (pre-dose) to time of last quantifiable concentration (0-24). |
Other
| Measure | Time frame | Description |
|---|---|---|
| Effect of Food on Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC (0-24)] | Pre-dose,0.5,1,2,4,6,8,18,20,24 hrs post-dose on Day 29 (fasted state), Day 30 (fed state) for once daily groups, pre-dose,0.5,1,2,4,6,8 hrs post-dose on Day 29 Day 29 (fasted state), Day 30 (fed state) for twice daily groups | AUC (0-24)= Area under the plasma concentration versus time curve from time zero (pre-dose) to time of last quantifiable concentration (0-24). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| PF-00337210 PF-00337210 0.67 mg, 1 mg, 2 mg, 4 mg, 6 mg, 8 mg or 9 mg capsule orally once daily or PF-00337210 4 mg or 6 mg capsule twice daily in cycles of 28 days. | 46 |
| Total | 46 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 |
|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 0 | 1 | 2 | 2 | 0 | 1 |
| Overall Study | Death | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Lack of Efficacy | 1 | 1 | 3 | 3 | 4 | 5 | 3 | 2 | 9 |
| Overall Study | Other | 0 | 0 | 0 | 0 | 1 | 0 | 3 | 1 | 2 |
| Overall Study | Physician Decision | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | PF-00337210 |
|---|---|
| Age Continuous | 53.9 years STANDARD_DEVIATION 13.1 |
| Sex: Female, Male Female | 21 Participants |
| Sex: Female, Male Male | 25 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 46 / 46 |
| serious Total, serious adverse events | 19 / 46 |
Outcome results
Primary
Maximum Administered Dose (MAD)
MAD: dose level at which 2 or more out of 6 participants experienced DLT during Cycle 1. DLTs: blood pressure of 180/110 mmHg or higher for 3 readings over 3 hours regardless of use of anti-hypertensive drugs or \>160/100 mmHg for 3 readings over 3 days on maximum anti-hypertensive drugs; afebrile Grade 4 neutropenia \>=7 days or \>= Grade 3 neutropenia associated with fever (1 reading of oral temperature \>38.5 degree C or 3 readings of oral temperature \>38.0 degree C in 24-hour period); Grade 4 thrombocytopenia; hemoptysis of \>1/2 teaspoon of bright red blood per day; proteinuria of \>=2 grams/24 hours; inability to resume PF-00337210 dosing at current dose level within 14 days of stopping due to treatment-related toxicity; \>=Grade 3 nonhematological toxicities (except alopecia and blood pressure/hypertension); Grade 3 nonhematological toxicities that could be controlled to Grade 2 or less with appropriate treatment were not considered dose limiting.
Time frame: Day 28
Population: Safety analysis set included all enrolled participants who received at least 1 dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PF-00337210 0.67 mg Once Daily | Maximum Administered Dose (MAD) | 9 mg once daily |
Primary
Maximum Tolerated Dose (MTD)
MTD: dose level at which no more than 1 of 6 participants experienced DLT during Cycle 1. DLTs: blood pressure of 180/110 mmHg or higher for 3 readings over 3 hours regardless of use of anti-hypertensive drugs or \>160/100 mmHg for 3 readings over 3 days on maximum anti-hypertensive drugs; afebrile Grade 4 neutropenia \>=7 days or \>= Grade 3 neutropenia associated with fever (1 reading of oral temperature \>38.5 degree C or 3 readings of oral temperature \>38.0 degree C in 24-hour period); Grade 4 thrombocytopenia; hemoptysis of \>1/2 teaspoon of bright red blood per day; proteinuria of \>=2 grams/24 hours; inability to resume PF-00337210 dosing at current dose level within 14 days of stopping due to treatment-related toxicity; \>=Grade 3 nonhematological toxicities (except alopecia and blood pressure/hypertension); Grade 3 nonhematological toxicities that could be controlled to Grade 2 or less with appropriate treatment were not considered dose limiting.
Time frame: Day 28
Population: Safety analysis set included all enrolled participants who received at least 1 dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PF-00337210 0.67 mg Once Daily | Maximum Tolerated Dose (MTD) | 8 mg once daily |
Primary
Number of Participants With Dose-limiting Toxicities (DLTs)
DLTs included events occurring in Cycle 1: blood pressure of 180/110 millimeters of mercury (mmHg) or higher for 3 readings over 3 hours regardless of use of anti-hypertensive drugs or greater than (\>) 160/100 mmHg for 3 readings over 3 days on maximum anti-hypertensive drugs; afebrile Grade 4 neutropenia for greater than or equal to (\>=) 7 days or \>=Grade 3 neutropenia associated with fever (1 reading of oral temperature \>38.5 degree Celsius \[degree C\] or 3 readings of oral temperature \>38.0 degree C in 24-hour period); Grade 4 thrombocytopenia; hemoptysis of \>1/2 teaspoon of bright red blood per day; proteinuria of \>=2 grams/24 hours; inability to resume PF-00337210 dosing at current dose level within 14 days of stopping due to treatment-related toxicity; \>=Grade 3 nonhematological toxicities (except alopecia and blood pressure/hypertension); Grade 3 nonhematological toxicities that could be controlled to Grade 2 or less with appropriate treatment were not considered dose limiting.
Time frame: Baseline up to Day 28
Population: Safety analysis set included all enrolled participants who received at least 1 dose of study medication. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PF-00337210 0.67 mg Once Daily | Number of Participants With Dose-limiting Toxicities (DLTs) | 0 participants |
| PF-00337210 1 mg Once Daily | Number of Participants With Dose-limiting Toxicities (DLTs) | 0 participants |
| PF-00337210 2 mg Once Daily | Number of Participants With Dose-limiting Toxicities (DLTs) | 0 participants |
| PF-00337210 4 mg Once Daily | Number of Participants With Dose-limiting Toxicities (DLTs) | 0 participants |
| PF-00337210 6 mg Once Daily | Number of Participants With Dose-limiting Toxicities (DLTs) | 0 participants |
| PF-00337210 8 mg Once Daily | Number of Participants With Dose-limiting Toxicities (DLTs) | 0 participants |
| PF-00337210 9 mg Once Daily | Number of Participants With Dose-limiting Toxicities (DLTs) | 2 participants |
| PF-00337210 4 mg Twice Daily | Number of Participants With Dose-limiting Toxicities (DLTs) | 0 participants |
| PF-00337210 6 mg Twice Daily | Number of Participants With Dose-limiting Toxicities (DLTs) | 1 participants |
Primary
Recommended Phase-2 Dose (RP2D)
RP2D was determined based on the safety profile and pharmacodynamic findings. The twice daily dosing was preferred over once daily dosing for RP2D, as per investigator's discretion, due to more consistent changes in pharmacodynamic markers and greater clinical benefit observed in twice daily dosing.
Time frame: Day 28
Population: Safety analysis set included all enrolled participants who received at least 1 dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PF-00337210 0.67 mg Once Daily | Recommended Phase-2 Dose (RP2D) | 6 mg twice daily |
Secondary
Apparent Volume of Distribution (Vss)
Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose is influenced by the fraction absorbed.
Time frame: Pre-dose,0.5,1,2,4,6,8,10,16,20,24 hrs post-dose on Day 1(0.67 mg group);pre-dose,0.5,1,2,4,6,8,18,20,24 hrs post-dose on Day 1,15,29(once daily groups);pre-dose,0.5,1,2,4,6,8 hrs post-dose on Day 1,15,29 (twice daily groups);pre-dose on Day 43, 57
Population: Formal quality-assured, quality-controlled, pharmacokinetic (PK) analysis was not performed and hence, Vss was not calculated.
Secondary
Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)]
AUC (0 - ∞)= Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - ∞). It is obtained from AUC (0 - t) plus AUC (t - ∞).
Time frame: Pre-dose,0.5,1,2,4,6,8,10,16,20,24 hrs post-dose on Day 1(0.67 mg group);pre-dose,0.5,1,2,4,6,8,18,20,24 hrs post-dose on Day 1,15,29(once daily groups);pre-dose,0.5,1,2,4,6,8 hrs post-dose on Day 1,15,29 (twice daily groups);pre-dose on Day 43, 57
Population: Formal quality-assured, quality-controlled, pharmacokinetic (PK) analysis was not performed and hence, AUC (0 - ∞) was not calculated.
Secondary
Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC (0-24)]
AUC (0-24)= Area under the plasma concentration versus time curve from time zero (pre-dose) to time of last quantifiable concentration (0-24).
Time frame: Pre-dose,0.5,1,2,4,6,8,10,16,20,24 hrs post-dose on Day 1(0.67 mg group);pre-dose,0.5,1,2,4,6,8,18,20,24 hrs post-dose on Day 1,15,29(once daily groups);pre-dose,0.5,1,2,4,6,8 hrs post-dose on Day 1,15,29 (twice daily groups);pre-dose on Day 43, 57
Population: Formal quality-assured, quality-controlled, pharmacokinetic (PK) analysis was not performed and hence, AUC (0-24) was not calculated.
Secondary
Change From Baseline in Biomarkers at Day 1 of Each Cycle up to Cycle 25
Biomarkers included soluble plasma proteins associated with angiogenesis (vascular endothelial growth factor \[VEGF\], soluble vascular endothelial growth factor-2 receptor \[sVEGFR2\], soluble vascular endothelial growth factor-3 receptor \[sVEGFR3\], soluble beta type platelet-derived growth factor \[sPDGFR beta\]) and tumor proliferation (soluble stem-cell factor receptor \[sKIT\])
Time frame: Baseline, Day 1 of Cycle 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25
Population: Results are not reported as the data were not statistically summarized but available in individual participant listing.
Secondary
Maximum Observed Plasma Concentration (Cmax)
Time frame: Pre-dose,0.5,1,2,4,6,8,10,16,20,24 hours(hrs) post-dose on Day 1(0.67 mg group);pre-dose,0.5,1,2,4,6,8,18,20,24 hrs post-dose on Day 1,15,29(once daily groups);pre-dose,0.5,1,2,4,6,8 hrs post-dose on Day 1,15,29 (twice daily groups);pre-dose on Day 43, 57
Population: Formal quality-assured, quality-controlled, pharmacokinetic (PK) analysis was not performed and hence, Cmax was not calculated.
Secondary
Number of Participants With Objective Response of Complete Response or Partial Response
Number of participants with objective response based on assessment of confirmed complete response (CR) or confirmed partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST). Confirmed CR defined as disappearance of all target and non-target lesions and no appearance of new lesions. Confirmed PR defined as at least 30 percent decrease in sum of the longest dimensions (LD) of the target lesions, taking as a reference the baseline sum LD, without progression of non-target lesions and no appearance of new lesions. Confirmed responses are those that persist on repeat imaging study \>=4 weeks after initial documentation of response.
Time frame: Baseline, every 8 weeks up to Cycle 25 (Week 100)
Population: Full Analysis set included all enrolled participants who received at least 1 dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PF-00337210 0.67 mg Once Daily | Number of Participants With Objective Response of Complete Response or Partial Response | 2 participants |
Secondary
Plasma Decay Half-Life (t1/2)
Plasma decay half-life is the time measured for the plasma concentration to decrease by one half.
Time frame: Pre-dose,0.5,1,2,4,6,8,10,16,20,24 hrs post-dose on Day 1(0.67 mg group);pre-dose,0.5,1,2,4,6,8,18,20,24 hrs post-dose on Day 1,15,29(once daily groups);pre-dose,0.5,1,2,4,6,8 hrs post-dose on Day 1,15,29 (twice daily groups);pre-dose on Day 43, 57
Population: Formal quality-assured, quality-controlled, pharmacokinetic (PK) analysis was not performed and hence, t1/2 was not calculated.
Secondary
Systemic Clearance (CL)
CL is a quantitative measure of the rate at which a drug substance is removed from the body.
Time frame: Pre-dose,0.5,1,2,4,6,8,10,16,20,24 hrs post-dose on Day 1(0.67 mg group);pre-dose,0.5,1,2,4,6,8,18,20,24 hrs post-dose on Day 1,15,29(once daily groups);pre-dose,0.5,1,2,4,6,8 hrs post-dose on Day 1,15,29 (twice daily groups);pre-dose on Day 43, 57
Population: Formal quality-assured, quality-controlled, PK analysis was not performed and hence, CL was not calculated.
Other Pre-specified
Effect of Food on Area Under the Curve From Time Zero to Last Quantifiable Concentration [AUC (0-24)]
AUC (0-24)= Area under the plasma concentration versus time curve from time zero (pre-dose) to time of last quantifiable concentration (0-24).
Time frame: Pre-dose,0.5,1,2,4,6,8,18,20,24 hrs post-dose on Day 29 (fasted state), Day 30 (fed state) for once daily groups, pre-dose,0.5,1,2,4,6,8 hrs post-dose on Day 29 Day 29 (fasted state), Day 30 (fed state) for twice daily groups
Population: Formal quality-assured, quality-controlled, PK analysis was not performed and hence, food effect on AUC (0-24) was not assessed.