Neoplasm
Conditions
Keywords
Oncology patients with advanced disease, BAY73-4506
Brief summary
Continuous dosing of BAY73-4506 in patients with advanced cancer
Interventions
DRUGEscalation cohort: Regorafenib (Stivarga, BAY73-4506) 20 mg
Participants in the dose-escalation cohort received a single 20 mg oral CP tablet of regorafenib on Day 1 of Cycle 1 followed by 1 day off treatment. On Day 3, once-daily continuous dosing with 20 mg oral co-precipitate (CP) tablets was initiated. A cycle was defined as 21 days. For Cycle 2 and subsequent cycles, regorafenib was administered once daily continuously on a 21-day cycle.
DRUGEscalation cohort: Regorafenib (Stivarga, BAY73-4506) 40 mg
Participants in the dose-escalation cohort received a single 40 mg oral CP tablet of regorafenib on Day 1 of Cycle 1 followed by 1 day off treatment. On Day 3, once-daily continuous dosing with 40 mg oral CP tablets was initiated. A cycle was defined as 21 days. For Cycle 2 and subsequent cycles, regorafenib was administered once daily continuously on a 21-day cycle.
DRUGEscalation cohort: Regorafenib (Stivarga, BAY73-4506) 100 mg
Participants in the dose-escalation cohort received a single 100 mg oral CP tablet of regorafenib on Day 1 of Cycle 1 followed by 1 day off treatment. On Day 3, once-daily continuous dosing with 100 mg oral CP tablets was initiated. A cycle was defined as 21 days. For Cycle 2 and subsequent cycles, regorafenib was administered once daily continuously on a 21-day cycle.
DRUGEscalation cohort: Regorafenib (Stivarga, BAY73-4506) 120 mg
Participants in the dose-escalation cohort received a single 120 mg oral CP tablet of regorafenib on Day 1 of Cycle 1 followed by 1 day off treatment. On Day 3, once-daily continuous dosing with 120 mg oral CP tablets was initiated. A cycle was defined as 21 days. For Cycle 2 and subsequent cycles, regorafenib was administered once daily continuously on a 21-day cycle.
DRUGEscalation cohort: Regorafenib (Stivarga, BAY73-4506) 140 mg
Participants in the dose-escalation cohort received a single 140 mg oral CP tablet of regorafenib on Day 1 of Cycle 1 followed by 1 day off treatment. On Day 3, once-daily continuous dosing with 140 mg oral CP tablets was initiated. A cycle was defined as 21 days. For Cycle 2 and subsequent cycles, regorafenib was administered once daily continuously on a 21-day cycle.
DRUGHCC Child-Pugh A expansion cohort: Regorafenib 100 mg
Hepatocellular carcinoma (HCC) Participants with Child Pugh A in the expansion cohort received a single 100 mg oral CP tablet of regorafenib on Day 1 of Cycle 1 followed by 1 day off treatment. On Day 3, once-daily continuous dosing with 100 mg oral CP tablets of regorafenib was initiated. A cycle was defined as 21 days. For Cycle 2 and subsequent cycles, regorafenib was administered once daily continuously on a 21-day cycle.
DRUGHCC Child-Pugh B expansion cohort: Regorafenib 100 mg
Hepatocellular carcinoma (HCC) Participants with Child Pugh B in the expansion cohort received a single 100 mg oral CP tablet of regorafenib on Day 1 of Cycle 1 followed by 1 day off treatment. On Day 3, once-daily continuous dosing with 100 mg oral CP tablets of regorafenib was initiated. A cycle was defined as 21 days. For Cycle 2 and subsequent cycles, regorafenib was administered once daily continuously on a 21-day cycle.
DRUGNSCLC expansion cohort: Regorafenib 100 mg
Non-small cell lung cancer (NSCLC) participants in the expansion cohort received a single 100 mg oral CP tablet of regorafenib on Day 1 of Cycle 1 followed by 1 day off treatment. On Day 3, once-daily continuous dosing with 100 mg oral CP tablets of regorafenib was initiated. A cycle was defined as 21 days. For Cycle 2 and subsequent cycles, regorafenib was administered once daily continuously on a 21-day cycle.
Sponsors
Bayer
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* 18 years * Patients with advanced, histologically or cytologically confirmed solid tumors, malignant lymphomas, or multiple myeloma refractory to any standard therapy * Radiographical, hematological or clinically evaluable tumor * Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2 * Life expectancy of at least 12 weeks * Adequate bone marrow, liver, and renal function as assessed by the following laboratory requirements: * Total bilirubin less than or equal to 1.5 x upper limit of normal (ULN) * Signed informed consent must be obtained prior to any study specific procedures
Exclusion criteria
* History of cardiac disease: congestive heart failure (CHF) \> New York Heart Association (NYHA) Class II; active coronary artery disease, myocardial infarction within 6 months prior to study entry; new onset angina within 3 months or unstable angina or cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted) * Uncontrolled hypertension defined as systolic blood pressure \> 150 mm Hg and/or diastolic blood pressure \> 90 mmHg, despite optimal medical management * History of HIV infection or chronic hepatitis B or C * Active clinically serious infections (\> Grade 2 NCI Common Terminology Criteria for Adverse Events v3.0) * Symptomatic metastatic brain or meningeal tumors unless the patient is \> 6 months from definitive therapy, has no evidence of tumor growth on an imaging study within 2 weeks prior to study entry and is clinically stable with respect to the tumor at the time of study entry. Patients with brain metastases must not be undergoing acute steroid therapy or steroid taper (chronic steroid therapy is acceptable provided that the dose is stable for one month prior to and following screening radiographic studies) * Substance abuse, medical, psychological or social conditions that may interfere with the patient178s participation in the study or evaluation of the study results * Radiotherapy to the target lesions within 3 weeks prior to Day 1, Cycle 1 (first dose of study drug). (Palliative radiotherapy will be allowed). Radiotherapy to the target lesions during study will be regarded as progressive disease * Previous or concurrent cancer which is distinct in primary site or histology from the cancer being evaluated in this study EXCEPT cervical carcinoma in situ, treated basal cell carcinoma, superficial bladder tumors \[Ta, Tis and T1\] or any cancer curatively treated \> 3 years prior to study entry.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose (MTD) | Within first 4 weeks of treatment | The MTD was defined as the highest dose level, which could be given to 6 participants such that no more than 1 participant (less than 33%) experienced a dose-limiting toxicity (DLT). |
| Maximum Observed Plasma Concentration After Single Dose Administration (Cmax) | Blood samples were collected on Cycle 1, Day 1. Samples were drawn at the following time points: 0 h pre-dose, 0.5, 1, 2, 4, 8, 10, 24, and 48 h post-dose | Cmax refers to the highest measured drug concentration, which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample. |
| Area Under the Concentration vs. Time Curve From Zero to Infinity After Single (First) Dose (AUC) | Blood samples were collected on Cycle 1, Day 1. Samples were drawn at the following time points: 0 h pre-dose, 0.5, 1, 2, 4, 8, 10, 24, and 48 h post-dose | The AUC is a measure of systemic drug exposure, which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample. |
| Cmax at Steady State During a Dosing Interval (Cmax,ss) | Blood samples were collected at on Cycle 2, Day 1 and on Cycle 3, Day 1 for expansion cohort. Samples were drawn at the following time points: 0 h pre-dose, 0.5, 1, 2, 4, 8, 10 and 24h post-dose. | Cmax,ss refers to the highest measured drug concentration, which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample, after multiple dose administration and after a steady state concentration has been reached. |
| AUC From Time 0 to 24 Hours at Steady State(AUC(0-24),ss) | Blood samples were collected on Cycle 2, Day 1 and on Cycle 3, Day 1 for expansion cohort. Samples were drawn at the following time points: 0 h pre-dose, 0.5, 1, 2, 4, 8, 10 and 24h post-dose. | AUC(0-24),ss is a measure of systemic drug exposure over 24 hours, which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample, after multiple dose administration and after a steady state concentration has been reached. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Biomarker Soluble Vascular Endothelial Growth Factor Receptor 2 (sCEGFR-2) Plasma Levels | No data obtained | The analysis of Biomarker sCEGFR-2 plasma levels is not done. |
| Ratio of Cmin,ss/Cmin (RACmin) | Blood samples were collected on Cycle 1, Day 1 and Cycle 2, Day 1 and on Cycle 3, Day 1 for expansion cohort. Samples were drawn at the following time points: 0 h pre-dose, 0.5, 1, 2, 4, 8, 10 and 24h post-dose | RACmin is the ratio of the lowest drug concentration at steady state to the lowest drug concentration after single dose administration. It is obtained by collecting a series of blood samples at various times after dosing, and measuring them for drug content. |
| Ratio of AUCt,ss/AUCt (RAAUC) | Blood samples were collected on Cycle 1, Day 1 and Cycle 2, Day 1 and on Cycle 3, Day 1 for expansion cohort. Samples were drawn at the following time points: 0 h pre-dose, 0.5, 1, 2, 4, 8, 10 and 24h post-dose | RAAUC is the ratio of the measure of systemic drug exposure over a specific dosing interval at steady state to the measure of systemic drug exposure over a specific dosing interval after single dose administration. It is obtained by collecting a series of blood samples at various times after dosing, and measuring them for drug content. |
| Ratio of AUCt,ss/AUC (RLIN) | Blood samples were collected on Cycle 1, Day 1 and Cycle 2, Day 1. Samples were drawn at the following time points: 0 h pre-dose, 0.5, 1, 2, 4, 8, 10 and 24h post-dose | RLIN is the ratio of the measure of systemic drug exposure at steady state to the measure of systemic drug exposure after single dose administration. It is obtained by collecting a series of blood samples at various times after dosing, and measuring them for drug content. |
| Biomarker Vascular Endothelial Growth Factor (VEGF) Plasma Levels | No data obtained | The analysis of Biomarker VEGF plasma levels is not done |
| AUC From Time 0 to the Last Data Point > Lower Limit of Quantification (LLOQ) (AUC(0-tlast)) | Blood samples were collected on Cycle 1, Day 1. Samples were drawn at the following time points: 0 h pre-dose, 0.5, 1, 2, 4, 8, 10, 24, and 48 h post-dose | The AUC(0-tlast) is a measure of systemic drug exposure from time 0 up to the time point at which the last measurable drug could be detectable, which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample. |
| Area Under the Concentration vs. Time Curve From Zero to Infinity After Single (First) Dose Divided by Dose (AUC/D) | Blood samples were collected on Cycle 1, Day 1. Samples were drawn at the following time points: 0 h pre-dose, 0.5, 1, 2, 4, 8, 10, 24, and 48 h post-dose | The AUC/D is a measure of systemic drug exposure (AUC) after the first single dose, which is then divided by that dose. It is obtained by collecting a series of blood samples at various times after dosing, and measuring them for drug content. |
| Maximum Observed Plasma Concentration After Single Dose Administration Divided by Dose (Cmax/D) | Blood samples were collected on Cycle 1, Day 1. Samples were drawn at the following time points: 0 h pre-dose, 0.5, 1, 2, 4, 8, 10, 24, and 48 h post-dose | Cmax/D refers to the highest measured drug concentration after a single dose administration, which is then divided by the administered dose. It is obtained by collecting a series of blood samples at various times after dosing, and measuring them for drug content. |
| Time to Reach Maximum Observed Plasma Concentration (Tmax) | Blood samples were collected on Cycle 1, Day 1. Samples were drawn at the following time points: 0 h pre-dose, 0.5, 1, 2, 4, 8, 10, 24, and 48 h post-dose. | Tmax refers to the time after dosing when a drug attains its highest measurable concentration (Cmax). It is obtained by collecting a series of blood samples at various times after dosing, and measuring them for drug content. |
| Half-life Associated With the Terminal Slope (T1/2) | Blood samples were collected on Cycle 1, Day 1. Samples were drawn at the following time points: 0 h pre-dose, 0.5, 1, 2, 4, 8, 10, 24, and 48 h post-dose. | T1/2 is the period of time required for the concentration or amount of drug in the body to be reduced to exactly one-half of a given concentration or amount. It is obtained by collecting a series of blood samples at various times after dosing, and measuring them for drug content. |
| Cmax at Steady State During a Dosing Interval Divided by Dose (Cmax,ss/D) | Blood samples were collected at on Cycle 2, Day 1 and on Cycle 3, Day 1 for expansion cohort. Samples were drawn at the following time points: 0 h pre-dose, 0.5, 1, 2, 4, 8, 10 and 24h post-dose | Cmax,ss/D refers to the highest measured drug concentration after multiple dose administration and after a steady state concentration has been reached, which is then divided by the administered dose. It is obtained by collecting a series of blood samples at various times after dosing, and measuring them for drug content. |
| AUC From Time 0 to 24 Hours at Steady State Divided by Dose (AUC(0-24)ss/D) | Blood samples were collected on Cycle 2, Day 1 and on Cycle 3, Day 1 for expansion cohort. Samples were drawn at the following time points: 0 h pre-dose, 0.5, 1, 2, 4, 8, 10 and 24h post-dose | AUC(0-24)ss/D is a measure of systemic drug exposure (AUC) over 24 hours after multiple dose administration and after a steady state concentration has been reached, which is then divided by the administered dose. It is obtained by collecting a series of blood samples at various times after dosing, and measuring them for drug content. |
| Time to Reach Maximum Observed Plasma Concentration at Steady State (Tmax,ss) | Blood samples were collected on Cycle 2, Day 1 and on Cycle 3, Day 1 for expansion cohort. Samples were drawn at the following time points: 0 h pre-dose, 0.5, 1, 2, 4, 8, 10 and 24h post-dose | Tmax,ss refers to the time after multiple dose administration and after a steady state concentration has been reached when a drug attains its highest measurable concentration (Cmax). It is obtained by collecting a series of blood samples at various times after dosing, and measuring them for drug content. |
| Ratio of Cmax,ss/Cmax (RACmax) | Blood samples were collected on Cycle 1, Day 1 and Cycle 2, Day 1 and on Cycle 3, Day 1 for expansion cohort. Samples were drawn at the following time points: 0 h pre-dose, 0.5, 1, 2, 4, 8, 10 and 24h post-dose | RACmax is the ratio of the highest drug concentration at steady state to the highest drug concentration after single dose administration. It is obtained by collecting a series of blood samples at various times after dosing, and measuring them for drug content. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Tumor Progression in Expansion Cohort | From the screening visit of the first participant until the last evaluation of the final participant over 6 years later, assessed at the screening visit, end of cycle 2, end of each even cycle and during the final visit (end of treatment) | Tumor progression evaluates changes in a tumor or tumors over time due to worsening of disease. Measurements and observations of the tumor status were performed before, during and after treatment. Tumor progression evaluates changes in a tumor or tumors over time due to worsening of disease. Measurements and observations of the tumor status were performed before, during and after treatment. Progression for solid tumors was evaluated based on the Response Evaluation Criteria in Solid Tumors (RECIST 1.0) criteria. Tumor dimensions were measured in millimeters and the longest diameter (LD) was recorded for up to 5 lesions per organ and 10 lesions total. A sum of the LD for all target lesions was recorded. The use of a 20% increase in the sum of LD of target lesions from the smallest sum or appearance of a new lesion was assessed as progression of disease. |
| Tumor Response in Dose Escalation Cohort | From the screening visit of the first participant until the last evaluation of the final participant over 6 years later, assessed at the screening visit, end of cycle 2, end of each even cycle and during the final visit (end of treatment) | Tumor Response (= Best Overall Response) of a participant was defined as the best tumor response (Complete Response (CR), Partial Response (PR), Stable Disease (SD), or Progressive Disease (PD)) observed during trial period assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. CR was defined as disappearance of tumor lesions, PR was defined as a decrease of at least 30% in the sum of tumor lesion sizes, SD was defined as steady state of disease, PD was defined as an increase of at least 20% in the sum of tumor lesions sizes. |
| Tumor Response in Expansion Cohort | From the screening visit of the first participant until the last evaluation of the final participant over 6 years later, assessed at the screening visit, end of cycle 2, end of each even cycle and during the final visit (end of treatment) | Tumor Response (= Best Overall Response) of a participant was defined as the best tumor response (Complete Response (CR), Partial Response (PR), Stable Disease (SD), or Progressive Disease (PD)) observed during trial period assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. CR was defined as disappearance of tumor lesions, PR was defined as a decrease of at least 30% in the sum of tumor lesion sizes, SD was defined as steady state of disease, PD was defined as an increase of at least 20% in the sum of tumor lesions sizes. |
| Tumor Progression in Dose Escalation Cohort | From the screening visit of the first participant until the last evaluation of the final participant over 6 years later, assessed at the screening visit, end of cycle 2, end of each even cycle and during the final visit (end of treatment) | Tumor progression evaluates changes in a tumor or tumors over time due to worsening of disease. Measurements and observations of the tumor status were performed before, during and after treatment. Progression for solid tumors was evaluated based on the Response Evaluation Criteria in Solid Tumors (RECIST 1.0) criteria. Tumor dimensions were measured in millimeters and the longest diameter (LD) was recorded for up to 5 lesions per organ and 10 lesions total. A sum of the LD for all target lesions was recorded. The use of a 20% increase in the sum of LD of target lesions from the smallest sum or appearance of a new lesion was assessed as progression of disease. |
Countries
United States
Participant flow
Recruitment details
Adult participants with advanced, histologically or cytologically confirmed solid tumors (including non-small-cell lung cancer (NSCLC) participants enrolled in the expansion portion of the study), malignant lymphomas, or multiple myeloma were enrolled in 5 centers in the USA from 01 FEB 2007 to 22 Apr 2011.
Pre-assignment details
109 (73 male and 36 female) participants were screened according to the inclusion and exclusion criteria to determine their appropriateness for inclusion in the study, and 86 (54 male and 32 female) participants were included at 5 centers, valid for safety population, 81 participants valid for ITT efficacy analysis and PK population.
Participants by arm
| Arm | Count |
|---|---|
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 20 mg Participants in the dose-escalation cohort received a single 20 mg oral CP tablet of regorafenib on Day 1 of Cycle 1 followed by 1 day off treatment. On Day 3, once-daily continuous dosing with 20 mg oral CP tablets was initiated. A cycle was defined as 21 days. For Cycle 2 and subsequent cycles, regorafenib was administered once daily continuously on a 21-day cycle. | 3 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 40 mg Participants in the dose-escalation cohort received a single 40 mg oral CP tablet of regorafenib on Day 1 of Cycle 1 followed by 1 day off treatment. On Day 3, once-daily continuous dosing with 20 mg oral CP tablets was initiated. A cycle was defined as 21 days. For Cycle 2 and subsequent cycles, regorafenib was administered once daily continuously on a 21-day cycle. | 8 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 100 mg Participants in the dose-escalation cohort received a single 100 mg oral CP tablet of regorafenib on Day 1 of Cycle 1 followed by 1 day off treatment. On Day 3, once-daily continuous dosing with 20 mg oral CP tablets was initiated. A cycle was defined as 21 days. For Cycle 2 and subsequent cycles, regorafenib was administered once daily continuously on a 21-day cycle. | 11 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 120 mg Participants in the dose-escalation cohort received a single 120 mg oral CP tablet of regorafenib on Day 1 of Cycle 1 followed by 1 day off treatment. On Day 3, once-daily continuous dosing with 20 mg oral CP tablets was initiated. A cycle was defined as 21 days. For Cycle 2 and subsequent cycles, regorafenib was administered once daily continuously on a 21-day cycle. | 6 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 140 mg Participants in the dose-escalation cohort received a single 140 mg oral CP tablet of regorafenib on Day 1 of Cycle 1 followed by 1 day off treatment. On Day 3, once-daily continuous dosing with 20 mg oral CP tablets was initiated. A cycle was defined as 21 days. For Cycle 2 and subsequent cycles, regorafenib was administered once daily continuously on a 21-day cycle. | 10 |
| HCC Child-Pugh A Expansion Cohort: Regorafenib 100 mg Hepatocellular carcinoma (HCC) Participants with Child Pugh A status in the expansion cohort received a single 100 mg oral CP tablet of regorafenib on Day 1 of Cycle 1 followed by 1 day off treatment. On Day 3, once-daily continuous dosing with 100 mg oral CP tablets of regorafenib was initiated. A cycle was defined as 21 days. For Cycle 2 and subsequent cycles, regorafenib was administered once daily continuously on a 21-day cycle. | 16 |
| HCC Child-Pugh B Expansion Cohort: Regorafenib 100 mg Hepatocellular carcinoma (HCC) Participants with Child Pugh B status in the expansion cohort received a single 100 mg oral CP tablet of regorafenib on Day 1 of Cycle 1 followed by 1 day off treatment. On Day 3, once-daily continuous dosing with 100 mg oral CP tablets of regorafenib was initiated. A cycle was defined as 21 days. For Cycle 2 and subsequent cycles, regorafenib was administered once daily continuously on a 21-day cycle. | 6 |
| NSCLC Expansion Cohort: Regorafenib 100 mg Non-small cell lung cancer (NSCLC) participants in the expansion cohort received a single 100 mg oral CP tablet of regorafenib on Day 1 of Cycle 1 followed by 1 day off treatment. On Day 3, once-daily continuous dosing with 100 mg oral CP tablets of regorafenib was initiated. A cycle was defined as 21 days. For Cycle 2 and subsequent cycles, regorafenib was administered once daily continuously on a 21-day cycle. | 26 |
| Total | 86 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 |
|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 2 | 4 | 0 | 2 | 0 | 0 | 2 |
| Overall Study | Disease progression, recurrence, relapse | 3 | 6 | 5 | 6 | 8 | 14 | 5 | 22 |
| Overall Study | Invest. text: completed all planned txs | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Non-compliance with study medication | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 2 | 0 | 0 | 1 | 1 | 1 |
Baseline characteristics
| Characteristic | Total | Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 20 mg | Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 40 mg | Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 100 mg | Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 120 mg | Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 140 mg | HCC Child-Pugh A Expansion Cohort: Regorafenib 100 mg | HCC Child-Pugh B Expansion Cohort: Regorafenib 100 mg | NSCLC Expansion Cohort: Regorafenib 100 mg |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 59.6 Years STANDARD_DEVIATION 11.8 | 63.3 Years STANDARD_DEVIATION 8.1 | 55.3 Years STANDARD_DEVIATION 13.1 | 61.9 Years STANDARD_DEVIATION 8.8 | 59.2 Years STANDARD_DEVIATION 10.7 | 55.7 Years STANDARD_DEVIATION 13.7 | 56.6 Years STANDARD_DEVIATION 13.2 | 56.7 Years STANDARD_DEVIATION 13.1 | 62.4 Years STANDARD_DEVIATION 12.2 |
| Sex: Female, Male Female | 32 Participants | 0 Participants | 3 Participants | 4 Participants | 3 Participants | 7 Participants | 4 Participants | 2 Participants | 9 Participants |
| Sex: Female, Male Male | 54 Participants | 3 Participants | 5 Participants | 7 Participants | 3 Participants | 3 Participants | 12 Participants | 4 Participants | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 2 / 3 | 8 / 8 | 58 / 59 | 5 / 6 | 10 / 10 |
| serious Total, serious adverse events | 0 / 3 | 3 / 8 | 31 / 59 | 3 / 6 | 6 / 10 |
Outcome results
Primary
Area Under the Concentration vs. Time Curve From Zero to Infinity After Single (First) Dose (AUC)
The AUC is a measure of systemic drug exposure, which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample.
Time frame: Blood samples were collected on Cycle 1, Day 1. Samples were drawn at the following time points: 0 h pre-dose, 0.5, 1, 2, 4, 8, 10, 24, and 48 h post-dose
Population: PK population; Number of Participants with at least one evaluable AUC were 5 (regorafenib) and 6 (M2) in 40mg; 5 (regorafenib and M2) in 100 mg; 3 (M2) in 120 mg; 6 (regorafenib and M2) in 140 mg; 9 (regorafenib), 10 (M2) and 1 (M5) in HCC Child Pugh A; 3 (regorafenib) and 2 (M2) in HCC Child Pugh B; 19 (regorafenib) and 16 (M2) in NSCLC
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Regorafenib, 20 mg, 40 mg, 100 mg, 120 mg, 140 mg | Area Under the Concentration vs. Time Curve From Zero to Infinity After Single (First) Dose (AUC) | Regorafenib (n=3,5,5,6,6,9,3,19) | NA mg*h/L | — |
| Regorafenib, 20 mg, 40 mg, 100 mg, 120 mg, 140 mg | Area Under the Concentration vs. Time Curve From Zero to Infinity After Single (First) Dose (AUC) | M5 (BAY81-8752) (n=3,8,10,6,10,1,4,24) | NA mg*h/L | — |
| Regorafenib, 20 mg, 40 mg, 100 mg, 120 mg, 140 mg | Area Under the Concentration vs. Time Curve From Zero to Infinity After Single (First) Dose (AUC) | M2 (BAY75-7495) (n=3,6,5,3,6,10,2,16) | NA mg*h/L | — |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 40 mg | Area Under the Concentration vs. Time Curve From Zero to Infinity After Single (First) Dose (AUC) | M5 (BAY81-8752) (n=3,8,10,6,10,1,4,24) | NA mg*h/L | — |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 40 mg | Area Under the Concentration vs. Time Curve From Zero to Infinity After Single (First) Dose (AUC) | M2 (BAY75-7495) (n=3,6,5,3,6,10,2,16) | 3.53 mg*h/L | Geometric Coefficient of Variation 161 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 40 mg | Area Under the Concentration vs. Time Curve From Zero to Infinity After Single (First) Dose (AUC) | Regorafenib (n=3,5,5,6,6,9,3,19) | 16.3 mg*h/L | Geometric Coefficient of Variation 76.3 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 100 mg | Area Under the Concentration vs. Time Curve From Zero to Infinity After Single (First) Dose (AUC) | M5 (BAY81-8752) (n=3,8,10,6,10,1,4,24) | NA mg*h/L | — |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 100 mg | Area Under the Concentration vs. Time Curve From Zero to Infinity After Single (First) Dose (AUC) | Regorafenib (n=3,5,5,6,6,9,3,19) | 43.7 mg*h/L | Geometric Coefficient of Variation 34.9 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 100 mg | Area Under the Concentration vs. Time Curve From Zero to Infinity After Single (First) Dose (AUC) | M2 (BAY75-7495) (n=3,6,5,3,6,10,2,16) | 12.8 mg*h/L | Geometric Coefficient of Variation 37 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 120 mg | Area Under the Concentration vs. Time Curve From Zero to Infinity After Single (First) Dose (AUC) | Regorafenib (n=3,5,5,6,6,9,3,19) | 52.9 mg*h/L | Geometric Coefficient of Variation 64.6 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 120 mg | Area Under the Concentration vs. Time Curve From Zero to Infinity After Single (First) Dose (AUC) | M2 (BAY75-7495) (n=3,6,5,3,6,10,2,16) | 21.0 mg*h/L | Geometric Coefficient of Variation 71.5 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 120 mg | Area Under the Concentration vs. Time Curve From Zero to Infinity After Single (First) Dose (AUC) | M5 (BAY81-8752) (n=3,8,10,6,10,1,4,24) | NA mg*h/L | — |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 140 mg | Area Under the Concentration vs. Time Curve From Zero to Infinity After Single (First) Dose (AUC) | M2 (BAY75-7495) (n=3,6,5,3,6,10,2,16) | 19.5 mg*h/L | Geometric Coefficient of Variation 20.3 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 140 mg | Area Under the Concentration vs. Time Curve From Zero to Infinity After Single (First) Dose (AUC) | Regorafenib (n=3,5,5,6,6,9,3,19) | 52.5 mg*h/L | Geometric Coefficient of Variation 66.4 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 140 mg | Area Under the Concentration vs. Time Curve From Zero to Infinity After Single (First) Dose (AUC) | M5 (BAY81-8752) (n=3,8,10,6,10,1,4,24) | NA mg*h/L | — |
| HCC Child-Pugh A Expansion Cohort: Regorafenib 100 mg | Area Under the Concentration vs. Time Curve From Zero to Infinity After Single (First) Dose (AUC) | M2 (BAY75-7495) (n=3,6,5,3,6,10,2,16) | 15.3 mg*h/L | Geometric Coefficient of Variation 69.9 |
| HCC Child-Pugh A Expansion Cohort: Regorafenib 100 mg | Area Under the Concentration vs. Time Curve From Zero to Infinity After Single (First) Dose (AUC) | Regorafenib (n=3,5,5,6,6,9,3,19) | 45.2 mg*h/L | Geometric Coefficient of Variation 84.3 |
| HCC Child-Pugh A Expansion Cohort: Regorafenib 100 mg | Area Under the Concentration vs. Time Curve From Zero to Infinity After Single (First) Dose (AUC) | M5 (BAY81-8752) (n=3,8,10,6,10,1,4,24) | 15.8 mg*h/L | — |
| HCC Child-Pugh B Expansion Cohort: Regorafenib 100 mg | Area Under the Concentration vs. Time Curve From Zero to Infinity After Single (First) Dose (AUC) | M2 (BAY75-7495) (n=3,6,5,3,6,10,2,16) | 27.2 mg*h/L | Geometric Coefficient of Variation 74.6 |
| HCC Child-Pugh B Expansion Cohort: Regorafenib 100 mg | Area Under the Concentration vs. Time Curve From Zero to Infinity After Single (First) Dose (AUC) | Regorafenib (n=3,5,5,6,6,9,3,19) | 57.7 mg*h/L | Geometric Coefficient of Variation 30.9 |
| HCC Child-Pugh B Expansion Cohort: Regorafenib 100 mg | Area Under the Concentration vs. Time Curve From Zero to Infinity After Single (First) Dose (AUC) | M5 (BAY81-8752) (n=3,8,10,6,10,1,4,24) | NA mg*h/L | — |
| NSCLC Expansion Cohort: Regorafenib 100 mg | Area Under the Concentration vs. Time Curve From Zero to Infinity After Single (First) Dose (AUC) | Regorafenib (n=3,5,5,6,6,9,3,19) | 33.5 mg*h/L | Geometric Coefficient of Variation 43.9 |
| NSCLC Expansion Cohort: Regorafenib 100 mg | Area Under the Concentration vs. Time Curve From Zero to Infinity After Single (First) Dose (AUC) | M2 (BAY75-7495) (n=3,6,5,3,6,10,2,16) | 11.6 mg*h/L | Geometric Coefficient of Variation 77.8 |
| NSCLC Expansion Cohort: Regorafenib 100 mg | Area Under the Concentration vs. Time Curve From Zero to Infinity After Single (First) Dose (AUC) | M5 (BAY81-8752) (n=3,8,10,6,10,1,4,24) | NA mg*h/L | — |
Primary
AUC From Time 0 to 24 Hours at Steady State(AUC(0-24),ss)
AUC(0-24),ss is a measure of systemic drug exposure over 24 hours, which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample, after multiple dose administration and after a steady state concentration has been reached.
Time frame: Blood samples were collected on Cycle 2, Day 1 and on Cycle 3, Day 1 for expansion cohort. Samples were drawn at the following time points: 0 h pre-dose, 0.5, 1, 2, 4, 8, 10 and 24h post-dose.
Population: Pharmacokinetic population; Number of Participants with an evaluable AUC(0-24),ss in at least one analyte in at least one analyte were 6 in 40mg; 6 in 100 mg; 2 in 120 mg; 3 in 140 mg; 0 in HCC Child Pugh A; 1 in HCC Child Pugh B; 5 in NSCLC
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Regorafenib, 20 mg, 40 mg, 100 mg, 120 mg, 140 mg | AUC From Time 0 to 24 Hours at Steady State(AUC(0-24),ss) | Regorafenib (n=3,6,6,2,3,0,1,5) | 12.9 mg*h/mL | Geometric Coefficient of Variation 21.2 |
| Regorafenib, 20 mg, 40 mg, 100 mg, 120 mg, 140 mg | AUC From Time 0 to 24 Hours at Steady State(AUC(0-24),ss) | M5 (BAY81-8752) (n=3,6,6,2,3,0,1,5) | 0.122 mg*h/mL | Geometric Coefficient of Variation 18.7 |
| Regorafenib, 20 mg, 40 mg, 100 mg, 120 mg, 140 mg | AUC From Time 0 to 24 Hours at Steady State(AUC(0-24),ss) | M2 (BAY75-7495) (n=3,6,6,2,3,0,1,5) | 1.11 mg*h/mL | Geometric Coefficient of Variation 42.9 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 40 mg | AUC From Time 0 to 24 Hours at Steady State(AUC(0-24),ss) | M5 (BAY81-8752) (n=3,6,6,2,3,0,1,5) | 2.22 mg*h/mL | Geometric Coefficient of Variation 136 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 40 mg | AUC From Time 0 to 24 Hours at Steady State(AUC(0-24),ss) | M2 (BAY75-7495) (n=3,6,6,2,3,0,1,5) | 7.20 mg*h/mL | Geometric Coefficient of Variation 56.7 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 40 mg | AUC From Time 0 to 24 Hours at Steady State(AUC(0-24),ss) | Regorafenib (n=3,6,6,2,3,0,1,5) | 18.1 mg*h/mL | Geometric Coefficient of Variation 35.9 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 100 mg | AUC From Time 0 to 24 Hours at Steady State(AUC(0-24),ss) | M5 (BAY81-8752) (n=3,6,6,2,3,0,1,5) | 18.6 mg*h/mL | Geometric Coefficient of Variation 58.1 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 100 mg | AUC From Time 0 to 24 Hours at Steady State(AUC(0-24),ss) | Regorafenib (n=3,6,6,2,3,0,1,5) | 49.6 mg*h/mL | Geometric Coefficient of Variation 18.5 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 100 mg | AUC From Time 0 to 24 Hours at Steady State(AUC(0-24),ss) | M2 (BAY75-7495) (n=3,6,6,2,3,0,1,5) | 31.5 mg*h/mL | Geometric Coefficient of Variation 25.2 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 120 mg | AUC From Time 0 to 24 Hours at Steady State(AUC(0-24),ss) | Regorafenib (n=3,6,6,2,3,0,1,5) | 40.6 mg*h/mL | Geometric Coefficient of Variation 32.9 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 120 mg | AUC From Time 0 to 24 Hours at Steady State(AUC(0-24),ss) | M2 (BAY75-7495) (n=3,6,6,2,3,0,1,5) | 40.9 mg*h/mL | Geometric Coefficient of Variation 245 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 120 mg | AUC From Time 0 to 24 Hours at Steady State(AUC(0-24),ss) | M5 (BAY81-8752) (n=3,6,6,2,3,0,1,5) | 44.4 mg*h/mL | Geometric Coefficient of Variation 3050 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 140 mg | AUC From Time 0 to 24 Hours at Steady State(AUC(0-24),ss) | M2 (BAY75-7495) (n=3,6,6,2,3,0,1,5) | 29.7 mg*h/mL | Geometric Coefficient of Variation 88.8 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 140 mg | AUC From Time 0 to 24 Hours at Steady State(AUC(0-24),ss) | Regorafenib (n=3,6,6,2,3,0,1,5) | 60.4 mg*h/mL | Geometric Coefficient of Variation 18.5 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 140 mg | AUC From Time 0 to 24 Hours at Steady State(AUC(0-24),ss) | M5 (BAY81-8752) (n=3,6,6,2,3,0,1,5) | 12.9 mg*h/mL | Geometric Coefficient of Variation 231 |
| HCC Child-Pugh A Expansion Cohort: Regorafenib 100 mg | AUC From Time 0 to 24 Hours at Steady State(AUC(0-24),ss) | M2 (BAY75-7495) (n=3,6,6,2,3,0,1,5) | NA mg*h/mL | — |
| HCC Child-Pugh A Expansion Cohort: Regorafenib 100 mg | AUC From Time 0 to 24 Hours at Steady State(AUC(0-24),ss) | Regorafenib (n=3,6,6,2,3,0,1,5) | NA mg*h/mL | — |
| HCC Child-Pugh A Expansion Cohort: Regorafenib 100 mg | AUC From Time 0 to 24 Hours at Steady State(AUC(0-24),ss) | M5 (BAY81-8752) (n=3,6,6,2,3,0,1,5) | NA mg*h/mL | — |
| HCC Child-Pugh B Expansion Cohort: Regorafenib 100 mg | AUC From Time 0 to 24 Hours at Steady State(AUC(0-24),ss) | M2 (BAY75-7495) (n=3,6,6,2,3,0,1,5) | 46.8 mg*h/mL | — |
| HCC Child-Pugh B Expansion Cohort: Regorafenib 100 mg | AUC From Time 0 to 24 Hours at Steady State(AUC(0-24),ss) | Regorafenib (n=3,6,6,2,3,0,1,5) | 39.2 mg*h/mL | — |
| HCC Child-Pugh B Expansion Cohort: Regorafenib 100 mg | AUC From Time 0 to 24 Hours at Steady State(AUC(0-24),ss) | M5 (BAY81-8752) (n=3,6,6,2,3,0,1,5) | 34.3 mg*h/mL | — |
| NSCLC Expansion Cohort: Regorafenib 100 mg | AUC From Time 0 to 24 Hours at Steady State(AUC(0-24),ss) | Regorafenib (n=3,6,6,2,3,0,1,5) | 35.8 mg*h/mL | Geometric Coefficient of Variation 83.9 |
| NSCLC Expansion Cohort: Regorafenib 100 mg | AUC From Time 0 to 24 Hours at Steady State(AUC(0-24),ss) | M2 (BAY75-7495) (n=3,6,6,2,3,0,1,5) | 14.6 mg*h/mL | Geometric Coefficient of Variation 104 |
| NSCLC Expansion Cohort: Regorafenib 100 mg | AUC From Time 0 to 24 Hours at Steady State(AUC(0-24),ss) | M5 (BAY81-8752) (n=3,6,6,2,3,0,1,5) | 6.17 mg*h/mL | Geometric Coefficient of Variation 133 |
Primary
Cmax at Steady State During a Dosing Interval (Cmax,ss)
Cmax,ss refers to the highest measured drug concentration, which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample, after multiple dose administration and after a steady state concentration has been reached.
Time frame: Blood samples were collected at on Cycle 2, Day 1 and on Cycle 3, Day 1 for expansion cohort. Samples were drawn at the following time points: 0 h pre-dose, 0.5, 1, 2, 4, 8, 10 and 24h post-dose.
Population: Pharmacokinetic population; Number of Participants with an evaluable Cmax,ss in at least one analyte were 6 in 40mg; 6 in 100 mg; 2 in 120 mg; 3 in 140 mg; 0 in HCC Child Pugh A; 1 in HCC Child Pugh B; 5 in NSCLC
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Regorafenib, 20 mg, 40 mg, 100 mg, 120 mg, 140 mg | Cmax at Steady State During a Dosing Interval (Cmax,ss) | Regorafenib (n=3,6,6,2,3,0,1,5) | 1.27 mg/L | Geometric Coefficient of Variation 19.4 |
| Regorafenib, 20 mg, 40 mg, 100 mg, 120 mg, 140 mg | Cmax at Steady State During a Dosing Interval (Cmax,ss) | M5 (BAY81-8752) (n=3,6,6,2,3,0,1,5) | 0.00911 mg/L | Geometric Coefficient of Variation 15.7 |
| Regorafenib, 20 mg, 40 mg, 100 mg, 120 mg, 140 mg | Cmax at Steady State During a Dosing Interval (Cmax,ss) | M2 (BAY75-7495) (n=3,6,6,2,3,0,1,5) | 0.0912 mg/L | Geometric Coefficient of Variation 39.5 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 40 mg | Cmax at Steady State During a Dosing Interval (Cmax,ss) | M5 (BAY81-8752) (n=3,6,6,2,3,0,1,5) | 0.174 mg/L | Geometric Coefficient of Variation 151 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 40 mg | Cmax at Steady State During a Dosing Interval (Cmax,ss) | M2 (BAY75-7495) (n=3,6,6,2,3,0,1,5) | 0.520 mg/L | Geometric Coefficient of Variation 74.3 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 40 mg | Cmax at Steady State During a Dosing Interval (Cmax,ss) | Regorafenib (n=3,6,6,2,3,0,1,5) | 1.50 mg/L | Geometric Coefficient of Variation 37 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 100 mg | Cmax at Steady State During a Dosing Interval (Cmax,ss) | M5 (BAY81-8752) (n=3,6,6,2,3,0,1,5) | 1.38 mg/L | Geometric Coefficient of Variation 87 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 100 mg | Cmax at Steady State During a Dosing Interval (Cmax,ss) | Regorafenib (n=3,6,6,2,3,0,1,5) | 4.27 mg/L | Geometric Coefficient of Variation 22.9 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 100 mg | Cmax at Steady State During a Dosing Interval (Cmax,ss) | M2 (BAY75-7495) (n=3,6,6,2,3,0,1,5) | 2.48 mg/L | Geometric Coefficient of Variation 36.3 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 120 mg | Cmax at Steady State During a Dosing Interval (Cmax,ss) | Regorafenib (n=3,6,6,2,3,0,1,5) | 3.62 mg/L | Geometric Coefficient of Variation 5.77 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 120 mg | Cmax at Steady State During a Dosing Interval (Cmax,ss) | M2 (BAY75-7495) (n=3,6,6,2,3,0,1,5) | 2.97 mg/L | Geometric Coefficient of Variation 217 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 120 mg | Cmax at Steady State During a Dosing Interval (Cmax,ss) | M5 (BAY81-8752) (n=3,6,6,2,3,0,1,5) | 3.29 mg/L | Geometric Coefficient of Variation 1400 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 140 mg | Cmax at Steady State During a Dosing Interval (Cmax,ss) | M2 (BAY75-7495) (n=3,6,6,2,3,0,1,5) | 2.20 mg/L | Geometric Coefficient of Variation 106 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 140 mg | Cmax at Steady State During a Dosing Interval (Cmax,ss) | Regorafenib (n=3,6,6,2,3,0,1,5) | 5.37 mg/L | Geometric Coefficient of Variation 30.9 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 140 mg | Cmax at Steady State During a Dosing Interval (Cmax,ss) | M5 (BAY81-8752) (n=3,6,6,2,3,0,1,5) | 0.948 mg/L | Geometric Coefficient of Variation 343 |
| HCC Child-Pugh A Expansion Cohort: Regorafenib 100 mg | Cmax at Steady State During a Dosing Interval (Cmax,ss) | M2 (BAY75-7495) (n=3,6,6,2,3,0,1,5) | NA mg/L | — |
| HCC Child-Pugh A Expansion Cohort: Regorafenib 100 mg | Cmax at Steady State During a Dosing Interval (Cmax,ss) | Regorafenib (n=3,6,6,2,3,0,1,5) | NA mg/L | — |
| HCC Child-Pugh A Expansion Cohort: Regorafenib 100 mg | Cmax at Steady State During a Dosing Interval (Cmax,ss) | M5 (BAY81-8752) (n=3,6,6,2,3,0,1,5) | NA mg/L | — |
| HCC Child-Pugh B Expansion Cohort: Regorafenib 100 mg | Cmax at Steady State During a Dosing Interval (Cmax,ss) | M2 (BAY75-7495) (n=3,6,6,2,3,0,1,5) | 2.40 mg/L | — |
| HCC Child-Pugh B Expansion Cohort: Regorafenib 100 mg | Cmax at Steady State During a Dosing Interval (Cmax,ss) | Regorafenib (n=3,6,6,2,3,0,1,5) | 2.69 mg/L | — |
| HCC Child-Pugh B Expansion Cohort: Regorafenib 100 mg | Cmax at Steady State During a Dosing Interval (Cmax,ss) | M5 (BAY81-8752) (n=3,6,6,2,3,0,1,5) | 1.59 mg/L | — |
| NSCLC Expansion Cohort: Regorafenib 100 mg | Cmax at Steady State During a Dosing Interval (Cmax,ss) | Regorafenib (n=3,6,6,2,3,0,1,5) | 2.55 mg/L | Geometric Coefficient of Variation 92.4 |
| NSCLC Expansion Cohort: Regorafenib 100 mg | Cmax at Steady State During a Dosing Interval (Cmax,ss) | M2 (BAY75-7495) (n=3,6,6,2,3,0,1,5) | 0.911 mg/L | Geometric Coefficient of Variation 126 |
| NSCLC Expansion Cohort: Regorafenib 100 mg | Cmax at Steady State During a Dosing Interval (Cmax,ss) | M5 (BAY81-8752) (n=3,6,6,2,3,0,1,5) | 0.349 mg/L | Geometric Coefficient of Variation 153 |
Primary
Maximum Observed Plasma Concentration After Single Dose Administration (Cmax)
Cmax refers to the highest measured drug concentration, which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample.
Time frame: Blood samples were collected on Cycle 1, Day 1. Samples were drawn at the following time points: 0 h pre-dose, 0.5, 1, 2, 4, 8, 10, 24, and 48 h post-dose
Population: Pharmacokinetic population; Number of Participants with an evaluable Cmax in at least one analyte was 1 (M5) in 20mg; 7 (regorafenib and M2) and 5 (M5) in 40mg; 13 (M5) in HCC Child-Pugh A; 22 (M5) in NSCLC
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Regorafenib, 20 mg, 40 mg, 100 mg, 120 mg, 140 mg | Maximum Observed Plasma Concentration After Single Dose Administration (Cmax) | Regorafenib (n=3,7,10,6,10,14,4,24) | 0.330 mg/L | Geometric Coefficient of Variation 14.8 |
| Regorafenib, 20 mg, 40 mg, 100 mg, 120 mg, 140 mg | Maximum Observed Plasma Concentration After Single Dose Administration (Cmax) | M5 (BAY81-8752) (n=1,5,10,6,10,13,4,22) | 0.00290 mg/L | — |
| Regorafenib, 20 mg, 40 mg, 100 mg, 120 mg, 140 mg | Maximum Observed Plasma Concentration After Single Dose Administration (Cmax) | M2 (BAY75-7495) (n=3,7,10,6,10,14,4,24) | 0.0181 mg/L | Geometric Coefficient of Variation 244 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 40 mg | Maximum Observed Plasma Concentration After Single Dose Administration (Cmax) | M5 (BAY81-8752) (n=1,5,10,6,10,13,4,22) | 0.00738 mg/L | Geometric Coefficient of Variation 124 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 40 mg | Maximum Observed Plasma Concentration After Single Dose Administration (Cmax) | M2 (BAY75-7495) (n=3,7,10,6,10,14,4,24) | 0.0867 mg/L | Geometric Coefficient of Variation 110 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 40 mg | Maximum Observed Plasma Concentration After Single Dose Administration (Cmax) | Regorafenib (n=3,7,10,6,10,14,4,24) | 0.422 mg/L | Geometric Coefficient of Variation 27.4 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 100 mg | Maximum Observed Plasma Concentration After Single Dose Administration (Cmax) | M5 (BAY81-8752) (n=1,5,10,6,10,13,4,22) | 0.0299 mg/L | Geometric Coefficient of Variation 118 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 100 mg | Maximum Observed Plasma Concentration After Single Dose Administration (Cmax) | Regorafenib (n=3,7,10,6,10,14,4,24) | 1.25 mg/L | Geometric Coefficient of Variation 30.7 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 100 mg | Maximum Observed Plasma Concentration After Single Dose Administration (Cmax) | M2 (BAY75-7495) (n=3,7,10,6,10,14,4,24) | 0.401 mg/L | Geometric Coefficient of Variation 51.2 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 120 mg | Maximum Observed Plasma Concentration After Single Dose Administration (Cmax) | Regorafenib (n=3,7,10,6,10,14,4,24) | 1.87 mg/L | Geometric Coefficient of Variation 24 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 120 mg | Maximum Observed Plasma Concentration After Single Dose Administration (Cmax) | M2 (BAY75-7495) (n=3,7,10,6,10,14,4,24) | 0.645 mg/L | Geometric Coefficient of Variation 43.2 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 120 mg | Maximum Observed Plasma Concentration After Single Dose Administration (Cmax) | M5 (BAY81-8752) (n=1,5,10,6,10,13,4,22) | 0.0459 mg/L | Geometric Coefficient of Variation 59.2 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 140 mg | Maximum Observed Plasma Concentration After Single Dose Administration (Cmax) | M2 (BAY75-7495) (n=3,7,10,6,10,14,4,24) | 0.606 mg/L | Geometric Coefficient of Variation 97.2 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 140 mg | Maximum Observed Plasma Concentration After Single Dose Administration (Cmax) | Regorafenib (n=3,7,10,6,10,14,4,24) | 1.90 mg/L | Geometric Coefficient of Variation 51.2 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 140 mg | Maximum Observed Plasma Concentration After Single Dose Administration (Cmax) | M5 (BAY81-8752) (n=1,5,10,6,10,13,4,22) | 0.0500 mg/L | Geometric Coefficient of Variation 140 |
| HCC Child-Pugh A Expansion Cohort: Regorafenib 100 mg | Maximum Observed Plasma Concentration After Single Dose Administration (Cmax) | M2 (BAY75-7495) (n=3,7,10,6,10,14,4,24) | 0.42 mg/L | Geometric Coefficient of Variation 154 |
| HCC Child-Pugh A Expansion Cohort: Regorafenib 100 mg | Maximum Observed Plasma Concentration After Single Dose Administration (Cmax) | Regorafenib (n=3,7,10,6,10,14,4,24) | 1.38 mg/L | Geometric Coefficient of Variation 98 |
| HCC Child-Pugh A Expansion Cohort: Regorafenib 100 mg | Maximum Observed Plasma Concentration After Single Dose Administration (Cmax) | M5 (BAY81-8752) (n=1,5,10,6,10,13,4,22) | 0.036 mg/L | Geometric Coefficient of Variation 110 |
| HCC Child-Pugh B Expansion Cohort: Regorafenib 100 mg | Maximum Observed Plasma Concentration After Single Dose Administration (Cmax) | M2 (BAY75-7495) (n=3,7,10,6,10,14,4,24) | 0.54 mg/L | Geometric Coefficient of Variation 129 |
| HCC Child-Pugh B Expansion Cohort: Regorafenib 100 mg | Maximum Observed Plasma Concentration After Single Dose Administration (Cmax) | Regorafenib (n=3,7,10,6,10,14,4,24) | 1.42 mg/L | Geometric Coefficient of Variation 76 |
| HCC Child-Pugh B Expansion Cohort: Regorafenib 100 mg | Maximum Observed Plasma Concentration After Single Dose Administration (Cmax) | M5 (BAY81-8752) (n=1,5,10,6,10,13,4,22) | 0.035 mg/L | Geometric Coefficient of Variation 352 |
| NSCLC Expansion Cohort: Regorafenib 100 mg | Maximum Observed Plasma Concentration After Single Dose Administration (Cmax) | Regorafenib (n=3,7,10,6,10,14,4,24) | 1.25 mg/L | Geometric Coefficient of Variation 68.5 |
| NSCLC Expansion Cohort: Regorafenib 100 mg | Maximum Observed Plasma Concentration After Single Dose Administration (Cmax) | M2 (BAY75-7495) (n=3,7,10,6,10,14,4,24) | 0.388 mg/L | Geometric Coefficient of Variation 190 |
| NSCLC Expansion Cohort: Regorafenib 100 mg | Maximum Observed Plasma Concentration After Single Dose Administration (Cmax) | M5 (BAY81-8752) (n=1,5,10,6,10,13,4,22) | 0.321 mg/L | Geometric Coefficient of Variation 142 |
Primary
Maximum Tolerated Dose (MTD)
The MTD was defined as the highest dose level, which could be given to 6 participants such that no more than 1 participant (less than 33%) experienced a dose-limiting toxicity (DLT).
Time frame: Within first 4 weeks of treatment
Population: Safety Population; dose escalation cohorts only
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Regorafenib, 20 mg, 40 mg, 100 mg, 120 mg, 140 mg | Maximum Tolerated Dose (MTD) | 100 mg |
Secondary
Area Under the Concentration vs. Time Curve From Zero to Infinity After Single (First) Dose Divided by Dose (AUC/D)
The AUC/D is a measure of systemic drug exposure (AUC) after the first single dose, which is then divided by that dose. It is obtained by collecting a series of blood samples at various times after dosing, and measuring them for drug content.
Time frame: Blood samples were collected on Cycle 1, Day 1. Samples were drawn at the following time points: 0 h pre-dose, 0.5, 1, 2, 4, 8, 10, 24, and 48 h post-dose
Population: PK population; Number of Participants with at least one evaluable AUC/D were 5 (regorafenib) and 6 (M-2) in 40mg; 5 (regorafenib and M-2) in 100 mg; 3 (M-2) in 120 mg; 6 (regorafenib and M-2) in 140 mg; 9 (regorafenib), 10 (M-2) and 1 (M5) in HCC Child Pugh A; 3 (regorafenib) and 2 (M-2) in HCC Child Pugh B; 19 (regorafenib) and 16 (M-2) in NSCLC
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Regorafenib, 20 mg, 40 mg, 100 mg, 120 mg, 140 mg | Area Under the Concentration vs. Time Curve From Zero to Infinity After Single (First) Dose Divided by Dose (AUC/D) | Regorafenib (n=3,5,5,6,6,9,3,19) | NA h/L | — |
| Regorafenib, 20 mg, 40 mg, 100 mg, 120 mg, 140 mg | Area Under the Concentration vs. Time Curve From Zero to Infinity After Single (First) Dose Divided by Dose (AUC/D) | M5 (BAY81-8752) (n=3,8,10,6,10,1,4,24) | NA h/L | — |
| Regorafenib, 20 mg, 40 mg, 100 mg, 120 mg, 140 mg | Area Under the Concentration vs. Time Curve From Zero to Infinity After Single (First) Dose Divided by Dose (AUC/D) | M2 (BAY75-7495) (n=3,6,5,3,6,10,2,16) | NA h/L | — |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 40 mg | Area Under the Concentration vs. Time Curve From Zero to Infinity After Single (First) Dose Divided by Dose (AUC/D) | M5 (BAY81-8752) (n=3,8,10,6,10,1,4,24) | NA h/L | — |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 40 mg | Area Under the Concentration vs. Time Curve From Zero to Infinity After Single (First) Dose Divided by Dose (AUC/D) | M2 (BAY75-7495) (n=3,6,5,3,6,10,2,16) | 0.0855 h/L | Geometric Coefficient of Variation 161 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 40 mg | Area Under the Concentration vs. Time Curve From Zero to Infinity After Single (First) Dose Divided by Dose (AUC/D) | Regorafenib (n=3,5,5,6,6,9,3,19) | 0.407 h/L | Geometric Coefficient of Variation 76.3 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 100 mg | Area Under the Concentration vs. Time Curve From Zero to Infinity After Single (First) Dose Divided by Dose (AUC/D) | M5 (BAY81-8752) (n=3,8,10,6,10,1,4,24) | NA h/L | — |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 100 mg | Area Under the Concentration vs. Time Curve From Zero to Infinity After Single (First) Dose Divided by Dose (AUC/D) | Regorafenib (n=3,5,5,6,6,9,3,19) | 0.437 h/L | Geometric Coefficient of Variation 34.9 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 100 mg | Area Under the Concentration vs. Time Curve From Zero to Infinity After Single (First) Dose Divided by Dose (AUC/D) | M2 (BAY75-7495) (n=3,6,5,3,6,10,2,16) | 0.124 h/L | Geometric Coefficient of Variation 37 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 120 mg | Area Under the Concentration vs. Time Curve From Zero to Infinity After Single (First) Dose Divided by Dose (AUC/D) | Regorafenib (n=3,5,5,6,6,9,3,19) | 0.441 h/L | Geometric Coefficient of Variation 64.6 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 120 mg | Area Under the Concentration vs. Time Curve From Zero to Infinity After Single (First) Dose Divided by Dose (AUC/D) | M2 (BAY75-7495) (n=3,6,5,3,6,10,2,16) | 0.169 h/L | Geometric Coefficient of Variation 71.5 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 120 mg | Area Under the Concentration vs. Time Curve From Zero to Infinity After Single (First) Dose Divided by Dose (AUC/D) | M5 (BAY81-8752) (n=3,8,10,6,10,1,4,24) | NA h/L | — |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 140 mg | Area Under the Concentration vs. Time Curve From Zero to Infinity After Single (First) Dose Divided by Dose (AUC/D) | M2 (BAY75-7495) (n=3,6,5,3,6,10,2,16) | 0.135 h/L | Geometric Coefficient of Variation 20.3 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 140 mg | Area Under the Concentration vs. Time Curve From Zero to Infinity After Single (First) Dose Divided by Dose (AUC/D) | Regorafenib (n=3,5,5,6,6,9,3,19) | 0.375 h/L | Geometric Coefficient of Variation 66.4 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 140 mg | Area Under the Concentration vs. Time Curve From Zero to Infinity After Single (First) Dose Divided by Dose (AUC/D) | M5 (BAY81-8752) (n=3,8,10,6,10,1,4,24) | NA h/L | — |
| HCC Child-Pugh A Expansion Cohort: Regorafenib 100 mg | Area Under the Concentration vs. Time Curve From Zero to Infinity After Single (First) Dose Divided by Dose (AUC/D) | M2 (BAY75-7495) (n=3,6,5,3,6,10,2,16) | 0.148 h/L | Geometric Coefficient of Variation 69.9 |
| HCC Child-Pugh A Expansion Cohort: Regorafenib 100 mg | Area Under the Concentration vs. Time Curve From Zero to Infinity After Single (First) Dose Divided by Dose (AUC/D) | Regorafenib (n=3,5,5,6,6,9,3,19) | 0.452 h/L | Geometric Coefficient of Variation 84.3 |
| HCC Child-Pugh A Expansion Cohort: Regorafenib 100 mg | Area Under the Concentration vs. Time Curve From Zero to Infinity After Single (First) Dose Divided by Dose (AUC/D) | M5 (BAY81-8752) (n=3,8,10,6,10,1,4,24) | 0.0157 h/L | — |
| HCC Child-Pugh B Expansion Cohort: Regorafenib 100 mg | Area Under the Concentration vs. Time Curve From Zero to Infinity After Single (First) Dose Divided by Dose (AUC/D) | M2 (BAY75-7495) (n=3,6,5,3,6,10,2,16) | 0.263 h/L | Geometric Coefficient of Variation 74.6 |
| HCC Child-Pugh B Expansion Cohort: Regorafenib 100 mg | Area Under the Concentration vs. Time Curve From Zero to Infinity After Single (First) Dose Divided by Dose (AUC/D) | Regorafenib (n=3,5,5,6,6,9,3,19) | 0.577 h/L | Geometric Coefficient of Variation 30.9 |
| HCC Child-Pugh B Expansion Cohort: Regorafenib 100 mg | Area Under the Concentration vs. Time Curve From Zero to Infinity After Single (First) Dose Divided by Dose (AUC/D) | M5 (BAY81-8752) (n=3,8,10,6,10,1,4,24) | NA h/L | — |
| NSCLC Expansion Cohort: Regorafenib 100 mg | Area Under the Concentration vs. Time Curve From Zero to Infinity After Single (First) Dose Divided by Dose (AUC/D) | Regorafenib (n=3,5,5,6,6,9,3,19) | 0.355 h/L | Geometric Coefficient of Variation 43.9 |
| NSCLC Expansion Cohort: Regorafenib 100 mg | Area Under the Concentration vs. Time Curve From Zero to Infinity After Single (First) Dose Divided by Dose (AUC/D) | M2 (BAY75-7495) (n=3,6,5,3,6,10,2,16) | 0.113 h/L | Geometric Coefficient of Variation 77.8 |
| NSCLC Expansion Cohort: Regorafenib 100 mg | Area Under the Concentration vs. Time Curve From Zero to Infinity After Single (First) Dose Divided by Dose (AUC/D) | M5 (BAY81-8752) (n=3,8,10,6,10,1,4,24) | NA h/L | — |
Secondary
AUC From Time 0 to 24 Hours at Steady State Divided by Dose (AUC(0-24)ss/D)
AUC(0-24)ss/D is a measure of systemic drug exposure (AUC) over 24 hours after multiple dose administration and after a steady state concentration has been reached, which is then divided by the administered dose. It is obtained by collecting a series of blood samples at various times after dosing, and measuring them for drug content.
Time frame: Blood samples were collected on Cycle 2, Day 1 and on Cycle 3, Day 1 for expansion cohort. Samples were drawn at the following time points: 0 h pre-dose, 0.5, 1, 2, 4, 8, 10 and 24h post-dose
Population: Pharmacokinetic population; Number of Participants with an evaluable AUC(0-24)ss/D in at least one analyte were 6 in 40mg; 6 in 100 mg; 2 in 120 mg; 3 in 140 mg; 0 in HCC Child Pugh A; 1 in HCC Child Pugh B; 5 in NSCLC
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Regorafenib, 20 mg, 40 mg, 100 mg, 120 mg, 140 mg | AUC From Time 0 to 24 Hours at Steady State Divided by Dose (AUC(0-24)ss/D) | Regorafenib (n=3,6,6,2,3,0,1,5) | 0.644 h/L | Geometric Coefficient of Variation 21.2 |
| Regorafenib, 20 mg, 40 mg, 100 mg, 120 mg, 140 mg | AUC From Time 0 to 24 Hours at Steady State Divided by Dose (AUC(0-24)ss/D) | M5 (BAY81-8752) (n=3,6,6,2,3,0,1,5) | 0.00609 h/L | Geometric Coefficient of Variation 18.7 |
| Regorafenib, 20 mg, 40 mg, 100 mg, 120 mg, 140 mg | AUC From Time 0 to 24 Hours at Steady State Divided by Dose (AUC(0-24)ss/D) | M2 (BAY75-7495) (n=3,6,6,2,3,0,1,5) | 0.0538 h/L | Geometric Coefficient of Variation 42.9 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 40 mg | AUC From Time 0 to 24 Hours at Steady State Divided by Dose (AUC(0-24)ss/D) | M5 (BAY81-8752) (n=3,6,6,2,3,0,1,5) | 0.0552 h/L | Geometric Coefficient of Variation 136 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 40 mg | AUC From Time 0 to 24 Hours at Steady State Divided by Dose (AUC(0-24)ss/D) | M2 (BAY75-7495) (n=3,6,6,2,3,0,1,5) | 0.174 h/L | Geometric Coefficient of Variation 56.7 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 40 mg | AUC From Time 0 to 24 Hours at Steady State Divided by Dose (AUC(0-24)ss/D) | Regorafenib (n=3,6,6,2,3,0,1,5) | 0.452 h/L | Geometric Coefficient of Variation 35.9 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 100 mg | AUC From Time 0 to 24 Hours at Steady State Divided by Dose (AUC(0-24)ss/D) | M5 (BAY81-8752) (n=3,6,6,2,3,0,1,5) | 0.185 h/L | Geometric Coefficient of Variation 58.1 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 100 mg | AUC From Time 0 to 24 Hours at Steady State Divided by Dose (AUC(0-24)ss/D) | Regorafenib (n=3,6,6,2,3,0,1,5) | 0.496 h/L | Geometric Coefficient of Variation 18.5 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 100 mg | AUC From Time 0 to 24 Hours at Steady State Divided by Dose (AUC(0-24)ss/D) | M2 (BAY75-7495) (n=3,6,6,2,3,0,1,5) | 0.305 h/L | Geometric Coefficient of Variation 25.2 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 120 mg | AUC From Time 0 to 24 Hours at Steady State Divided by Dose (AUC(0-24)ss/D) | Regorafenib (n=3,6,6,2,3,0,1,5) | 0.338 h/L | Geometric Coefficient of Variation 32.9 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 120 mg | AUC From Time 0 to 24 Hours at Steady State Divided by Dose (AUC(0-24)ss/D) | M2 (BAY75-7495) (n=3,6,6,2,3,0,1,5) | 0.330 h/L | Geometric Coefficient of Variation 245 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 120 mg | AUC From Time 0 to 24 Hours at Steady State Divided by Dose (AUC(0-24)ss/D) | M5 (BAY81-8752) (n=3,6,6,2,3,0,1,5) | 0.368 h/L | Geometric Coefficient of Variation 3050 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 140 mg | AUC From Time 0 to 24 Hours at Steady State Divided by Dose (AUC(0-24)ss/D) | M2 (BAY75-7495) (n=3,6,6,2,3,0,1,5) | 0.205 h/L | Geometric Coefficient of Variation 88.8 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 140 mg | AUC From Time 0 to 24 Hours at Steady State Divided by Dose (AUC(0-24)ss/D) | Regorafenib (n=3,6,6,2,3,0,1,5) | 0.431 h/L | Geometric Coefficient of Variation 18.5 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 140 mg | AUC From Time 0 to 24 Hours at Steady State Divided by Dose (AUC(0-24)ss/D) | M5 (BAY81-8752) (n=3,6,6,2,3,0,1,5) | 0.0916 h/L | Geometric Coefficient of Variation 231 |
| HCC Child-Pugh A Expansion Cohort: Regorafenib 100 mg | AUC From Time 0 to 24 Hours at Steady State Divided by Dose (AUC(0-24)ss/D) | M2 (BAY75-7495) (n=3,6,6,2,3,0,1,5) | NA h/L | — |
| HCC Child-Pugh A Expansion Cohort: Regorafenib 100 mg | AUC From Time 0 to 24 Hours at Steady State Divided by Dose (AUC(0-24)ss/D) | Regorafenib (n=3,6,6,2,3,0,1,5) | NA h/L | — |
| HCC Child-Pugh A Expansion Cohort: Regorafenib 100 mg | AUC From Time 0 to 24 Hours at Steady State Divided by Dose (AUC(0-24)ss/D) | M5 (BAY81-8752) (n=3,6,6,2,3,0,1,5) | NA h/L | — |
| HCC Child-Pugh B Expansion Cohort: Regorafenib 100 mg | AUC From Time 0 to 24 Hours at Steady State Divided by Dose (AUC(0-24)ss/D) | M2 (BAY75-7495) (n=3,6,6,2,3,0,1,5) | 0.453 h/L | — |
| HCC Child-Pugh B Expansion Cohort: Regorafenib 100 mg | AUC From Time 0 to 24 Hours at Steady State Divided by Dose (AUC(0-24)ss/D) | Regorafenib (n=3,6,6,2,3,0,1,5) | 0.392 h/L | — |
| HCC Child-Pugh B Expansion Cohort: Regorafenib 100 mg | AUC From Time 0 to 24 Hours at Steady State Divided by Dose (AUC(0-24)ss/D) | M5 (BAY81-8752) (n=3,6,6,2,3,0,1,5) | 0.342 h/L | — |
| NSCLC Expansion Cohort: Regorafenib 100 mg | AUC From Time 0 to 24 Hours at Steady State Divided by Dose (AUC(0-24)ss/D) | Regorafenib (n=3,6,6,2,3,0,1,5) | 0.358 h/L | Geometric Coefficient of Variation 83.8 |
| NSCLC Expansion Cohort: Regorafenib 100 mg | AUC From Time 0 to 24 Hours at Steady State Divided by Dose (AUC(0-24)ss/D) | M2 (BAY75-7495) (n=3,6,6,2,3,0,1,5) | 0.141 h/L | Geometric Coefficient of Variation 104 |
| NSCLC Expansion Cohort: Regorafenib 100 mg | AUC From Time 0 to 24 Hours at Steady State Divided by Dose (AUC(0-24)ss/D) | M5 (BAY81-8752) (n=3,6,6,2,3,0,1,5) | 0.0615 h/L | Geometric Coefficient of Variation 133 |
Secondary
AUC From Time 0 to the Last Data Point > Lower Limit of Quantification (LLOQ) (AUC(0-tlast))
The AUC(0-tlast) is a measure of systemic drug exposure from time 0 up to the time point at which the last measurable drug could be detectable, which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample.
Time frame: Blood samples were collected on Cycle 1, Day 1. Samples were drawn at the following time points: 0 h pre-dose, 0.5, 1, 2, 4, 8, 10, 24, and 48 h post-dose
Population: Pharmacokinetic population; Number of Participants with an evaluable AUC(0-tlast) in at least one analyte were 1(M-5) in 20mg; 7 (regorafenib and M-2) and 5 (M-5) in 40mg; 13 (M-5) in HCC Child Pugh A; 22 (M5) in NSCLC
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Regorafenib, 20 mg, 40 mg, 100 mg, 120 mg, 140 mg | AUC From Time 0 to the Last Data Point > Lower Limit of Quantification (LLOQ) (AUC(0-tlast)) | Regorafenib (n=3,7,10,6,10,14,4,24) | 7.98 mg*h/L | Geometric Coefficient of Variation 28 |
| Regorafenib, 20 mg, 40 mg, 100 mg, 120 mg, 140 mg | AUC From Time 0 to the Last Data Point > Lower Limit of Quantification (LLOQ) (AUC(0-tlast)) | M5 (BAY81-8752) (n=1,5,10,6,10,13,4,22) | 0.0275 mg*h/L | — |
| Regorafenib, 20 mg, 40 mg, 100 mg, 120 mg, 140 mg | AUC From Time 0 to the Last Data Point > Lower Limit of Quantification (LLOQ) (AUC(0-tlast)) | M2 (BAY75-7495) (n=3,7,10,6,10,14,4,24) | 0.384 mg*h/L | Geometric Coefficient of Variation 330 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 40 mg | AUC From Time 0 to the Last Data Point > Lower Limit of Quantification (LLOQ) (AUC(0-tlast)) | M5 (BAY81-8752) (n=1,5,10,6,10,13,4,22) | 0.165 mg*h/L | Geometric Coefficient of Variation 254 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 40 mg | AUC From Time 0 to the Last Data Point > Lower Limit of Quantification (LLOQ) (AUC(0-tlast)) | M2 (BAY75-7495) (n=3,7,10,6,10,14,4,24) | 2.02 mg*h/L | Geometric Coefficient of Variation 108 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 40 mg | AUC From Time 0 to the Last Data Point > Lower Limit of Quantification (LLOQ) (AUC(0-tlast)) | Regorafenib (n=3,7,10,6,10,14,4,24) | 9.12 mg*h/L | Geometric Coefficient of Variation 38.8 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 100 mg | AUC From Time 0 to the Last Data Point > Lower Limit of Quantification (LLOQ) (AUC(0-tlast)) | M5 (BAY81-8752) (n=1,5,10,6,10,13,4,22) | 0.976 mg*h/L | Geometric Coefficient of Variation 111 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 100 mg | AUC From Time 0 to the Last Data Point > Lower Limit of Quantification (LLOQ) (AUC(0-tlast)) | Regorafenib (n=3,7,10,6,10,14,4,24) | 32.7 mg*h/L | Geometric Coefficient of Variation 37.9 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 100 mg | AUC From Time 0 to the Last Data Point > Lower Limit of Quantification (LLOQ) (AUC(0-tlast)) | M2 (BAY75-7495) (n=3,7,10,6,10,14,4,24) | 11.3 mg*h/L | Geometric Coefficient of Variation 47.4 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 120 mg | AUC From Time 0 to the Last Data Point > Lower Limit of Quantification (LLOQ) (AUC(0-tlast)) | Regorafenib (n=3,7,10,6,10,14,4,24) | 33.5 mg*h/L | Geometric Coefficient of Variation 60.4 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 120 mg | AUC From Time 0 to the Last Data Point > Lower Limit of Quantification (LLOQ) (AUC(0-tlast)) | M2 (BAY75-7495) (n=3,7,10,6,10,14,4,24) | 14.2 mg*h/L | Geometric Coefficient of Variation 53.4 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 120 mg | AUC From Time 0 to the Last Data Point > Lower Limit of Quantification (LLOQ) (AUC(0-tlast)) | M5 (BAY81-8752) (n=1,5,10,6,10,13,4,22) | 1.51 mg*h/L | Geometric Coefficient of Variation 71.1 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 140 mg | AUC From Time 0 to the Last Data Point > Lower Limit of Quantification (LLOQ) (AUC(0-tlast)) | M2 (BAY75-7495) (n=3,7,10,6,10,14,4,24) | 13.6 mg*h/L | Geometric Coefficient of Variation 82.6 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 140 mg | AUC From Time 0 to the Last Data Point > Lower Limit of Quantification (LLOQ) (AUC(0-tlast)) | Regorafenib (n=3,7,10,6,10,14,4,24) | 35.8 mg*h/L | Geometric Coefficient of Variation 57 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 140 mg | AUC From Time 0 to the Last Data Point > Lower Limit of Quantification (LLOQ) (AUC(0-tlast)) | M5 (BAY81-8752) (n=1,5,10,6,10,13,4,22) | 1.54 mg*h/L | Geometric Coefficient of Variation 71.1 |
| HCC Child-Pugh A Expansion Cohort: Regorafenib 100 mg | AUC From Time 0 to the Last Data Point > Lower Limit of Quantification (LLOQ) (AUC(0-tlast)) | M2 (BAY75-7495) (n=3,7,10,6,10,14,4,24) | 8.84 mg*h/L | Geometric Coefficient of Variation 122 |
| HCC Child-Pugh A Expansion Cohort: Regorafenib 100 mg | AUC From Time 0 to the Last Data Point > Lower Limit of Quantification (LLOQ) (AUC(0-tlast)) | Regorafenib (n=3,7,10,6,10,14,4,24) | 26.8 mg*h/L | Geometric Coefficient of Variation 67.5 |
| HCC Child-Pugh A Expansion Cohort: Regorafenib 100 mg | AUC From Time 0 to the Last Data Point > Lower Limit of Quantification (LLOQ) (AUC(0-tlast)) | M5 (BAY81-8752) (n=1,5,10,6,10,13,4,22) | 1.02 mg*h/L | Geometric Coefficient of Variation 122 |
| HCC Child-Pugh B Expansion Cohort: Regorafenib 100 mg | AUC From Time 0 to the Last Data Point > Lower Limit of Quantification (LLOQ) (AUC(0-tlast)) | M2 (BAY75-7495) (n=3,7,10,6,10,14,4,24) | 13.4 mg*h/L | Geometric Coefficient of Variation 194 |
| HCC Child-Pugh B Expansion Cohort: Regorafenib 100 mg | AUC From Time 0 to the Last Data Point > Lower Limit of Quantification (LLOQ) (AUC(0-tlast)) | Regorafenib (n=3,7,10,6,10,14,4,24) | 33.0 mg*h/L | Geometric Coefficient of Variation 112 |
| HCC Child-Pugh B Expansion Cohort: Regorafenib 100 mg | AUC From Time 0 to the Last Data Point > Lower Limit of Quantification (LLOQ) (AUC(0-tlast)) | M5 (BAY81-8752) (n=1,5,10,6,10,13,4,22) | 0.821 mg*h/L | Geometric Coefficient of Variation 587 |
| NSCLC Expansion Cohort: Regorafenib 100 mg | AUC From Time 0 to the Last Data Point > Lower Limit of Quantification (LLOQ) (AUC(0-tlast)) | Regorafenib (n=3,7,10,6,10,14,4,24) | 18.7 mg*h/L | Geometric Coefficient of Variation 55.3 |
| NSCLC Expansion Cohort: Regorafenib 100 mg | AUC From Time 0 to the Last Data Point > Lower Limit of Quantification (LLOQ) (AUC(0-tlast)) | M2 (BAY75-7495) (n=3,7,10,6,10,14,4,24) | 6.54 mg*h/L | Geometric Coefficient of Variation 156 |
| NSCLC Expansion Cohort: Regorafenib 100 mg | AUC From Time 0 to the Last Data Point > Lower Limit of Quantification (LLOQ) (AUC(0-tlast)) | M5 (BAY81-8752) (n=1,5,10,6,10,13,4,22) | 0.821 mg*h/L | Geometric Coefficient of Variation 254 |
Secondary
Biomarker Soluble Vascular Endothelial Growth Factor Receptor 2 (sCEGFR-2) Plasma Levels
The analysis of Biomarker sCEGFR-2 plasma levels is not done.
Time frame: No data obtained
Population: ITT
Secondary
Biomarker Vascular Endothelial Growth Factor (VEGF) Plasma Levels
The analysis of Biomarker VEGF plasma levels is not done
Time frame: No data obtained
Population: ITT
Secondary
Cmax at Steady State During a Dosing Interval Divided by Dose (Cmax,ss/D)
Cmax,ss/D refers to the highest measured drug concentration after multiple dose administration and after a steady state concentration has been reached, which is then divided by the administered dose. It is obtained by collecting a series of blood samples at various times after dosing, and measuring them for drug content.
Time frame: Blood samples were collected at on Cycle 2, Day 1 and on Cycle 3, Day 1 for expansion cohort. Samples were drawn at the following time points: 0 h pre-dose, 0.5, 1, 2, 4, 8, 10 and 24h post-dose
Population: Pharmacokinetic population; Number of Participants with an evaluable Cmax,ss/D in at least one analyte were 6 in 40mg; 6 in 100 mg; 2 in 120 mg; 3 in 140 mg; 0 in HCC Child Pugh A; 1 in HCC Child Pugh B; 5 in NSCLC
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Regorafenib, 20 mg, 40 mg, 100 mg, 120 mg, 140 mg | Cmax at Steady State During a Dosing Interval Divided by Dose (Cmax,ss/D) | Regorafenib (n=3,6,6,2,3,0,1,5) | 0.0636 1/L | Geometric Coefficient of Variation 19.4 |
| Regorafenib, 20 mg, 40 mg, 100 mg, 120 mg, 140 mg | Cmax at Steady State During a Dosing Interval Divided by Dose (Cmax,ss/D) | M5 (BAY81-8752) (n=3,6,6,2,3,0,1,5) | 0.000454 1/L | Geometric Coefficient of Variation 15.7 |
| Regorafenib, 20 mg, 40 mg, 100 mg, 120 mg, 140 mg | Cmax at Steady State During a Dosing Interval Divided by Dose (Cmax,ss/D) | M2 (BAY75-7495) (n=3,6,6,2,3,0,1,5) | 0.00441 1/L | Geometric Coefficient of Variation 39.5 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 40 mg | Cmax at Steady State During a Dosing Interval Divided by Dose (Cmax,ss/D) | M5 (BAY81-8752) (n=3,6,6,2,3,0,1,5) | 0.00434 1/L | Geometric Coefficient of Variation 151 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 40 mg | Cmax at Steady State During a Dosing Interval Divided by Dose (Cmax,ss/D) | M2 (BAY75-7495) (n=3,6,6,2,3,0,1,5) | 0.0126 1/L | Geometric Coefficient of Variation 74.3 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 40 mg | Cmax at Steady State During a Dosing Interval Divided by Dose (Cmax,ss/D) | Regorafenib (n=3,6,6,2,3,0,1,5) | 0.0374 1/L | Geometric Coefficient of Variation 37 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 100 mg | Cmax at Steady State During a Dosing Interval Divided by Dose (Cmax,ss/D) | M5 (BAY81-8752) (n=3,6,6,2,3,0,1,5) | 0.0137 1/L | Geometric Coefficient of Variation 87.9 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 100 mg | Cmax at Steady State During a Dosing Interval Divided by Dose (Cmax,ss/D) | Regorafenib (n=3,6,6,2,3,0,1,5) | 0.0427 1/L | Geometric Coefficient of Variation 22.9 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 100 mg | Cmax at Steady State During a Dosing Interval Divided by Dose (Cmax,ss/D) | M2 (BAY75-7495) (n=3,6,6,2,3,0,1,5) | 0.0241 1/L | Geometric Coefficient of Variation 36.3 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 120 mg | Cmax at Steady State During a Dosing Interval Divided by Dose (Cmax,ss/D) | Regorafenib (n=3,6,6,2,3,0,1,5) | 0.0302 1/L | Geometric Coefficient of Variation 5.77 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 120 mg | Cmax at Steady State During a Dosing Interval Divided by Dose (Cmax,ss/D) | M2 (BAY75-7495) (n=3,6,6,2,3,0,1,5) | 0.0240 1/L | Geometric Coefficient of Variation 217 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 120 mg | Cmax at Steady State During a Dosing Interval Divided by Dose (Cmax,ss/D) | M5 (BAY81-8752) (n=3,6,6,2,3,0,1,5) | 0.0273 1/L | Geometric Coefficient of Variation 1400 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 140 mg | Cmax at Steady State During a Dosing Interval Divided by Dose (Cmax,ss/D) | M2 (BAY75-7495) (n=3,6,6,2,3,0,1,5) | 0.0152 1/L | Geometric Coefficient of Variation 106 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 140 mg | Cmax at Steady State During a Dosing Interval Divided by Dose (Cmax,ss/D) | Regorafenib (n=3,6,6,2,3,0,1,5) | 0.0383 1/L | Geometric Coefficient of Variation 30.9 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 140 mg | Cmax at Steady State During a Dosing Interval Divided by Dose (Cmax,ss/D) | M5 (BAY81-8752) (n=3,6,6,2,3,0,1,5) | 0.00674 1/L | Geometric Coefficient of Variation 343 |
| HCC Child-Pugh A Expansion Cohort: Regorafenib 100 mg | Cmax at Steady State During a Dosing Interval Divided by Dose (Cmax,ss/D) | M2 (BAY75-7495) (n=3,6,6,2,3,0,1,5) | NA 1/L | — |
| HCC Child-Pugh A Expansion Cohort: Regorafenib 100 mg | Cmax at Steady State During a Dosing Interval Divided by Dose (Cmax,ss/D) | Regorafenib (n=3,6,6,2,3,0,1,5) | NA 1/L | — |
| HCC Child-Pugh A Expansion Cohort: Regorafenib 100 mg | Cmax at Steady State During a Dosing Interval Divided by Dose (Cmax,ss/D) | M5 (BAY81-8752) (n=3,6,6,2,3,0,1,5) | NA 1/L | — |
| HCC Child-Pugh B Expansion Cohort: Regorafenib 100 mg | Cmax at Steady State During a Dosing Interval Divided by Dose (Cmax,ss/D) | M2 (BAY75-7495) (n=3,6,6,2,3,0,1,5) | 0.0232 1/L | — |
| HCC Child-Pugh B Expansion Cohort: Regorafenib 100 mg | Cmax at Steady State During a Dosing Interval Divided by Dose (Cmax,ss/D) | Regorafenib (n=3,6,6,2,3,0,1,5) | 0.0269 1/L | — |
| HCC Child-Pugh B Expansion Cohort: Regorafenib 100 mg | Cmax at Steady State During a Dosing Interval Divided by Dose (Cmax,ss/D) | M5 (BAY81-8752) (n=3,6,6,2,3,0,1,5) | 0.0159 1/L | — |
| NSCLC Expansion Cohort: Regorafenib 100 mg | Cmax at Steady State During a Dosing Interval Divided by Dose (Cmax,ss/D) | Regorafenib (n=3,6,6,2,3,0,1,5) | 0.0255 1/L | Geometric Coefficient of Variation 92.4 |
| NSCLC Expansion Cohort: Regorafenib 100 mg | Cmax at Steady State During a Dosing Interval Divided by Dose (Cmax,ss/D) | M2 (BAY75-7495) (n=3,6,6,2,3,0,1,5) | 0.00881 1/L | Geometric Coefficient of Variation 126 |
| NSCLC Expansion Cohort: Regorafenib 100 mg | Cmax at Steady State During a Dosing Interval Divided by Dose (Cmax,ss/D) | M5 (BAY81-8752) (n=3,6,6,2,3,0,1,5) | 0.00347 1/L | Geometric Coefficient of Variation 153 |
Secondary
Half-life Associated With the Terminal Slope (T1/2)
T1/2 is the period of time required for the concentration or amount of drug in the body to be reduced to exactly one-half of a given concentration or amount. It is obtained by collecting a series of blood samples at various times after dosing, and measuring them for drug content.
Time frame: Blood samples were collected on Cycle 1, Day 1. Samples were drawn at the following time points: 0 h pre-dose, 0.5, 1, 2, 4, 8, 10, 24, and 48 h post-dose.
Population: PK population; Number of Patients with at least an evaluable T1/2 were 5 (regorafenib) and 6 (M2) in 40mg; 5 (regorafenib and M2) in 100 mg; 3 (regorafenib and M2) in 120 mg; 6 (regorafenib and M2) in 140 mg; 9 (regorafenib), 10(M2) and 1 (M5) in HCC Child Pugh A; 3 (regorafenib) and 2 (M2) in HCC Child Pugh B; 19 (regorafenib) and 16 (M2) in NSCLC
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Regorafenib, 20 mg, 40 mg, 100 mg, 120 mg, 140 mg | Half-life Associated With the Terminal Slope (T1/2) | Regorafenib (n=3,5,5,3,6,9,22,19) | NA h | — |
| Regorafenib, 20 mg, 40 mg, 100 mg, 120 mg, 140 mg | Half-life Associated With the Terminal Slope (T1/2) | M5 (BAY81-8752) (n=3,8,10,6,10,1,4,24) | NA h | — |
| Regorafenib, 20 mg, 40 mg, 100 mg, 120 mg, 140 mg | Half-life Associated With the Terminal Slope (T1/2) | M2 (BAY75-7495) (n=3,6,5,3,6,10,2,16) | NA h | — |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 40 mg | Half-life Associated With the Terminal Slope (T1/2) | M5 (BAY81-8752) (n=3,8,10,6,10,1,4,24) | NA h | — |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 40 mg | Half-life Associated With the Terminal Slope (T1/2) | M2 (BAY75-7495) (n=3,6,5,3,6,10,2,16) | 40.3 h | Geometric Coefficient of Variation 52.3 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 40 mg | Half-life Associated With the Terminal Slope (T1/2) | Regorafenib (n=3,5,5,3,6,9,22,19) | 41.6 h | Geometric Coefficient of Variation 41.1 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 100 mg | Half-life Associated With the Terminal Slope (T1/2) | M5 (BAY81-8752) (n=3,8,10,6,10,1,4,24) | NA h | — |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 100 mg | Half-life Associated With the Terminal Slope (T1/2) | Regorafenib (n=3,5,5,3,6,9,22,19) | 31.6 h | Geometric Coefficient of Variation 32.5 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 100 mg | Half-life Associated With the Terminal Slope (T1/2) | M2 (BAY75-7495) (n=3,6,5,3,6,10,2,16) | 24.8 h | Geometric Coefficient of Variation 28.6 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 120 mg | Half-life Associated With the Terminal Slope (T1/2) | Regorafenib (n=3,5,5,3,6,9,22,19) | 27.7 h | Geometric Coefficient of Variation 47.8 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 120 mg | Half-life Associated With the Terminal Slope (T1/2) | M2 (BAY75-7495) (n=3,6,5,3,6,10,2,16) | 22.9 h | Geometric Coefficient of Variation 27.6 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 120 mg | Half-life Associated With the Terminal Slope (T1/2) | M5 (BAY81-8752) (n=3,8,10,6,10,1,4,24) | NA h | — |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 140 mg | Half-life Associated With the Terminal Slope (T1/2) | M2 (BAY75-7495) (n=3,6,5,3,6,10,2,16) | 22.7 h | Geometric Coefficient of Variation 64.7 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 140 mg | Half-life Associated With the Terminal Slope (T1/2) | Regorafenib (n=3,5,5,3,6,9,22,19) | 23.2 h | Geometric Coefficient of Variation 43.6 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 140 mg | Half-life Associated With the Terminal Slope (T1/2) | M5 (BAY81-8752) (n=3,8,10,6,10,1,4,24) | NA h | — |
| HCC Child-Pugh A Expansion Cohort: Regorafenib 100 mg | Half-life Associated With the Terminal Slope (T1/2) | M2 (BAY75-7495) (n=3,6,5,3,6,10,2,16) | 24.0 h | Geometric Coefficient of Variation 56.3 |
| HCC Child-Pugh A Expansion Cohort: Regorafenib 100 mg | Half-life Associated With the Terminal Slope (T1/2) | Regorafenib (n=3,5,5,3,6,9,22,19) | 25.2 h | Geometric Coefficient of Variation 52 |
| HCC Child-Pugh A Expansion Cohort: Regorafenib 100 mg | Half-life Associated With the Terminal Slope (T1/2) | M5 (BAY81-8752) (n=3,8,10,6,10,1,4,24) | 68.7 h | — |
| HCC Child-Pugh B Expansion Cohort: Regorafenib 100 mg | Half-life Associated With the Terminal Slope (T1/2) | M2 (BAY75-7495) (n=3,6,5,3,6,10,2,16) | 19.2 h | Geometric Coefficient of Variation 16.4 |
| HCC Child-Pugh B Expansion Cohort: Regorafenib 100 mg | Half-life Associated With the Terminal Slope (T1/2) | Regorafenib (n=3,5,5,3,6,9,22,19) | 745.3 h | Geometric Coefficient of Variation 79.7 |
| HCC Child-Pugh B Expansion Cohort: Regorafenib 100 mg | Half-life Associated With the Terminal Slope (T1/2) | M5 (BAY81-8752) (n=3,8,10,6,10,1,4,24) | NA h | — |
| NSCLC Expansion Cohort: Regorafenib 100 mg | Half-life Associated With the Terminal Slope (T1/2) | Regorafenib (n=3,5,5,3,6,9,22,19) | 33.3 h | Geometric Coefficient of Variation 64.8 |
| NSCLC Expansion Cohort: Regorafenib 100 mg | Half-life Associated With the Terminal Slope (T1/2) | M2 (BAY75-7495) (n=3,6,5,3,6,10,2,16) | 26.4 h | Geometric Coefficient of Variation 73.4 |
| NSCLC Expansion Cohort: Regorafenib 100 mg | Half-life Associated With the Terminal Slope (T1/2) | M5 (BAY81-8752) (n=3,8,10,6,10,1,4,24) | NA h | — |
Secondary
Maximum Observed Plasma Concentration After Single Dose Administration Divided by Dose (Cmax/D)
Cmax/D refers to the highest measured drug concentration after a single dose administration, which is then divided by the administered dose. It is obtained by collecting a series of blood samples at various times after dosing, and measuring them for drug content.
Time frame: Blood samples were collected on Cycle 1, Day 1. Samples were drawn at the following time points: 0 h pre-dose, 0.5, 1, 2, 4, 8, 10, 24, and 48 h post-dose
Population: Pharmacokinetic population; Number of Participants with an evaluable Cmax/D in at least one analyte was 1 (M5) in 20mg; 7 (regorafenib and M2) and 5 (M5) in 40mg; 13 (M5) in HCC Child-Pugh A; 22 (M5) in NSCLC
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Regorafenib, 20 mg, 40 mg, 100 mg, 120 mg, 140 mg | Maximum Observed Plasma Concentration After Single Dose Administration Divided by Dose (Cmax/D) | Regorafenib (n=3,7,10,6,10,14,4,24) | 0.0165 1/L | Geometric Coefficient of Variation 14.8 |
| Regorafenib, 20 mg, 40 mg, 100 mg, 120 mg, 140 mg | Maximum Observed Plasma Concentration After Single Dose Administration Divided by Dose (Cmax/D) | M5 (BAY81-8752) (n=1,5,10,6,10,13,4,22) | 0.000114 1/L | — |
| Regorafenib, 20 mg, 40 mg, 100 mg, 120 mg, 140 mg | Maximum Observed Plasma Concentration After Single Dose Administration Divided by Dose (Cmax/D) | M2 (BAY75-7495) (n=3,7,10,6,10,14,4,24) | 0.000874 1/L | Geometric Coefficient of Variation 244 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 40 mg | Maximum Observed Plasma Concentration After Single Dose Administration Divided by Dose (Cmax/D) | M5 (BAY81-8752) (n=1,5,10,6,10,13,4,22) | 0.000184 1/L | Geometric Coefficient of Variation 124 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 40 mg | Maximum Observed Plasma Concentration After Single Dose Administration Divided by Dose (Cmax/D) | M2 (BAY75-7495) (n=3,7,10,6,10,14,4,24) | 0.00210 1/L | Geometric Coefficient of Variation 110 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 40 mg | Maximum Observed Plasma Concentration After Single Dose Administration Divided by Dose (Cmax/D) | Regorafenib (n=3,7,10,6,10,14,4,24) | 0.0106 1/L | Geometric Coefficient of Variation 27.4 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 100 mg | Maximum Observed Plasma Concentration After Single Dose Administration Divided by Dose (Cmax/D) | M5 (BAY81-8752) (n=1,5,10,6,10,13,4,22) | 0.000298 1/L | Geometric Coefficient of Variation 118 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 100 mg | Maximum Observed Plasma Concentration After Single Dose Administration Divided by Dose (Cmax/D) | Regorafenib (n=3,7,10,6,10,14,4,24) | 0.0125 1/L | Geometric Coefficient of Variation 30.7 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 100 mg | Maximum Observed Plasma Concentration After Single Dose Administration Divided by Dose (Cmax/D) | M2 (BAY75-7495) (n=3,7,10,6,10,14,4,24) | 0.00388 1/L | Geometric Coefficient of Variation 51.2 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 120 mg | Maximum Observed Plasma Concentration After Single Dose Administration Divided by Dose (Cmax/D) | Regorafenib (n=3,7,10,6,10,14,4,24) | 0.0156 1/L | Geometric Coefficient of Variation 24 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 120 mg | Maximum Observed Plasma Concentration After Single Dose Administration Divided by Dose (Cmax/D) | M2 (BAY75-7495) (n=3,7,10,6,10,14,4,24) | 0.00520 1/L | Geometric Coefficient of Variation 43.2 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 120 mg | Maximum Observed Plasma Concentration After Single Dose Administration Divided by Dose (Cmax/D) | M5 (BAY81-8752) (n=1,5,10,6,10,13,4,22) | 0.000381 1/L | Geometric Coefficient of Variation 59.2 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 140 mg | Maximum Observed Plasma Concentration After Single Dose Administration Divided by Dose (Cmax/D) | M2 (BAY75-7495) (n=3,7,10,6,10,14,4,24) | 0.00419 1/L | Geometric Coefficient of Variation 97.2 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 140 mg | Maximum Observed Plasma Concentration After Single Dose Administration Divided by Dose (Cmax/D) | Regorafenib (n=3,7,10,6,10,14,4,24) | 0.0136 1/L | Geometric Coefficient of Variation 51.2 |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 140 mg | Maximum Observed Plasma Concentration After Single Dose Administration Divided by Dose (Cmax/D) | M5 (BAY81-8752) (n=1,5,10,6,10,13,4,22) | 0.000355 1/L | Geometric Coefficient of Variation 140 |
| HCC Child-Pugh A Expansion Cohort: Regorafenib 100 mg | Maximum Observed Plasma Concentration After Single Dose Administration Divided by Dose (Cmax/D) | M2 (BAY75-7495) (n=3,7,10,6,10,14,4,24) | 0.00404 1/L | Geometric Coefficient of Variation 154 |
| HCC Child-Pugh A Expansion Cohort: Regorafenib 100 mg | Maximum Observed Plasma Concentration After Single Dose Administration Divided by Dose (Cmax/D) | Regorafenib (n=3,7,10,6,10,14,4,24) | 0.0138 1/L | Geometric Coefficient of Variation 97.9 |
| HCC Child-Pugh A Expansion Cohort: Regorafenib 100 mg | Maximum Observed Plasma Concentration After Single Dose Administration Divided by Dose (Cmax/D) | M5 (BAY81-8752) (n=1,5,10,6,10,13,4,22) | 0.000355 1/L | Geometric Coefficient of Variation 110 |
| HCC Child-Pugh B Expansion Cohort: Regorafenib 100 mg | Maximum Observed Plasma Concentration After Single Dose Administration Divided by Dose (Cmax/D) | M2 (BAY75-7495) (n=3,7,10,6,10,14,4,24) | 0.00526 1/L | Geometric Coefficient of Variation 129 |
| HCC Child-Pugh B Expansion Cohort: Regorafenib 100 mg | Maximum Observed Plasma Concentration After Single Dose Administration Divided by Dose (Cmax/D) | Regorafenib (n=3,7,10,6,10,14,4,24) | 0.0142 1/L | Geometric Coefficient of Variation 76.1 |
| HCC Child-Pugh B Expansion Cohort: Regorafenib 100 mg | Maximum Observed Plasma Concentration After Single Dose Administration Divided by Dose (Cmax/D) | M5 (BAY81-8752) (n=1,5,10,6,10,13,4,22) | 0.000351 1/L | Geometric Coefficient of Variation 352 |
| NSCLC Expansion Cohort: Regorafenib 100 mg | Maximum Observed Plasma Concentration After Single Dose Administration Divided by Dose (Cmax/D) | Regorafenib (n=3,7,10,6,10,14,4,24) | 0.0125 1/L | Geometric Coefficient of Variation 68.5 |
| NSCLC Expansion Cohort: Regorafenib 100 mg | Maximum Observed Plasma Concentration After Single Dose Administration Divided by Dose (Cmax/D) | M2 (BAY75-7495) (n=3,7,10,6,10,14,4,24) | 0.00376 1/L | Geometric Coefficient of Variation 190 |
| NSCLC Expansion Cohort: Regorafenib 100 mg | Maximum Observed Plasma Concentration After Single Dose Administration Divided by Dose (Cmax/D) | M5 (BAY81-8752) (n=1,5,10,6,10,13,4,22) | 0.000320 1/L | Geometric Coefficient of Variation 142 |
Secondary
Ratio of AUCt,ss/AUC (RLIN)
RLIN is the ratio of the measure of systemic drug exposure at steady state to the measure of systemic drug exposure after single dose administration. It is obtained by collecting a series of blood samples at various times after dosing, and measuring them for drug content.
Time frame: Blood samples were collected on Cycle 1, Day 1 and Cycle 2, Day 1. Samples were drawn at the following time points: 0 h pre-dose, 0.5, 1, 2, 4, 8, 10 and 24h post-dose
Population: PK population; Number of Participants with an evaluable AUCt,ss and AUC in at least one analyte were 0 in 20mg; 3 (regorafenib) and 4 (M2) in 40mg; 3 in 100 mg; 2 (regorafenib) and 0 (M2) in 120 mg; 3 (regorafenib) and 2 (M2) in 140 mg; 0 in HCC Child Pugh A; 1 in HCC Child Pugh B; 4 in NSCLC; No participants have evaluable data for M5.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Regorafenib, 20 mg, 40 mg, 100 mg, 120 mg, 140 mg | Ratio of AUCt,ss/AUC (RLIN) | M2 (BAY75-7495) (n=0,4,3,0,2,0,1,4) | NA Ratio |
| Regorafenib, 20 mg, 40 mg, 100 mg, 120 mg, 140 mg | Ratio of AUCt,ss/AUC (RLIN) | Regorafenib (n=0,3,3,2,3,0,1,4) | NA Ratio |
| Regorafenib, 20 mg, 40 mg, 100 mg, 120 mg, 140 mg | Ratio of AUCt,ss/AUC (RLIN) | M5 (BAY81-8752) (n=0) | NA Ratio |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 40 mg | Ratio of AUCt,ss/AUC (RLIN) | M5 (BAY81-8752) (n=0) | NA Ratio |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 40 mg | Ratio of AUCt,ss/AUC (RLIN) | M2 (BAY75-7495) (n=0,4,3,0,2,0,1,4) | 1.63 Ratio |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 40 mg | Ratio of AUCt,ss/AUC (RLIN) | Regorafenib (n=0,3,3,2,3,0,1,4) | 1.53 Ratio |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 100 mg | Ratio of AUCt,ss/AUC (RLIN) | Regorafenib (n=0,3,3,2,3,0,1,4) | 1.27 Ratio |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 100 mg | Ratio of AUCt,ss/AUC (RLIN) | M5 (BAY81-8752) (n=0) | NA Ratio |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 100 mg | Ratio of AUCt,ss/AUC (RLIN) | M2 (BAY75-7495) (n=0,4,3,0,2,0,1,4) | 2.13 Ratio |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 120 mg | Ratio of AUCt,ss/AUC (RLIN) | M2 (BAY75-7495) (n=0,4,3,0,2,0,1,4) | NA Ratio |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 120 mg | Ratio of AUCt,ss/AUC (RLIN) | Regorafenib (n=0,3,3,2,3,0,1,4) | 0.600 Ratio |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 120 mg | Ratio of AUCt,ss/AUC (RLIN) | M5 (BAY81-8752) (n=0) | NA Ratio |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 140 mg | Ratio of AUCt,ss/AUC (RLIN) | Regorafenib (n=0,3,3,2,3,0,1,4) | 2.20 Ratio |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 140 mg | Ratio of AUCt,ss/AUC (RLIN) | M5 (BAY81-8752) (n=0) | NA Ratio |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 140 mg | Ratio of AUCt,ss/AUC (RLIN) | M2 (BAY75-7495) (n=0,4,3,0,2,0,1,4) | 1.39 Ratio |
| HCC Child-Pugh A Expansion Cohort: Regorafenib 100 mg | Ratio of AUCt,ss/AUC (RLIN) | M2 (BAY75-7495) (n=0,4,3,0,2,0,1,4) | NA Ratio |
| HCC Child-Pugh A Expansion Cohort: Regorafenib 100 mg | Ratio of AUCt,ss/AUC (RLIN) | M5 (BAY81-8752) (n=0) | NA Ratio |
| HCC Child-Pugh A Expansion Cohort: Regorafenib 100 mg | Ratio of AUCt,ss/AUC (RLIN) | Regorafenib (n=0,3,3,2,3,0,1,4) | NA Ratio |
| HCC Child-Pugh B Expansion Cohort: Regorafenib 100 mg | Ratio of AUCt,ss/AUC (RLIN) | Regorafenib (n=0,3,3,2,3,0,1,4) | 0.800 Ratio |
| HCC Child-Pugh B Expansion Cohort: Regorafenib 100 mg | Ratio of AUCt,ss/AUC (RLIN) | M2 (BAY75-7495) (n=0,4,3,0,2,0,1,4) | 2.70 Ratio |
| HCC Child-Pugh B Expansion Cohort: Regorafenib 100 mg | Ratio of AUCt,ss/AUC (RLIN) | M5 (BAY81-8752) (n=0) | NA Ratio |
| NSCLC Expansion Cohort: Regorafenib 100 mg | Ratio of AUCt,ss/AUC (RLIN) | M2 (BAY75-7495) (n=0,4,3,0,2,0,1,4) | 1.27 Ratio |
| NSCLC Expansion Cohort: Regorafenib 100 mg | Ratio of AUCt,ss/AUC (RLIN) | Regorafenib (n=0,3,3,2,3,0,1,4) | 1.11 Ratio |
| NSCLC Expansion Cohort: Regorafenib 100 mg | Ratio of AUCt,ss/AUC (RLIN) | M5 (BAY81-8752) (n=0) | NA Ratio |
Secondary
Ratio of AUCt,ss/AUCt (RAAUC)
RAAUC is the ratio of the measure of systemic drug exposure over a specific dosing interval at steady state to the measure of systemic drug exposure over a specific dosing interval after single dose administration. It is obtained by collecting a series of blood samples at various times after dosing, and measuring them for drug content.
Time frame: Blood samples were collected on Cycle 1, Day 1 and Cycle 2, Day 1 and on Cycle 3, Day 1 for expansion cohort. Samples were drawn at the following time points: 0 h pre-dose, 0.5, 1, 2, 4, 8, 10 and 24h post-dose
Population: Pharmacokinetic population; Number of Participants with an evaluable AUCt,ss and AUCt in at least one analyte were 0 (M5) in 20mg; 5 (regorafenib and M2) and 4 (M5) in 40mg; 6 in 100 mg; 2 in 120 mg; 3 in 140 mg; 0 in HCC Child Pugh A; 1 in HCC Child Pugh B; 5 in NSCLC
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Regorafenib, 20 mg, 40 mg, 100 mg, 120 mg, 140 mg | Ratio of AUCt,ss/AUCt (RAAUC) | Regorafenib (n=3,5,6,2,3,0,1,5) | 3.20 Ratio |
| Regorafenib, 20 mg, 40 mg, 100 mg, 120 mg, 140 mg | Ratio of AUCt,ss/AUCt (RAAUC) | M5 (BAY81-8752) (n=0,4,,6,2,3,0,1,5) | NA Ratio |
| Regorafenib, 20 mg, 40 mg, 100 mg, 120 mg, 140 mg | Ratio of AUCt,ss/AUCt (RAAUC) | M2 (BAY75-7495) (n=3,5,6,2,3,0,1,5) | 5.79 Ratio |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 40 mg | Ratio of AUCt,ss/AUCt (RAAUC) | M5 (BAY81-8752) (n=0,4,,6,2,3,0,1,5) | 28.1 Ratio |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 40 mg | Ratio of AUCt,ss/AUCt (RAAUC) | M2 (BAY75-7495) (n=3,5,6,2,3,0,1,5) | 4.72 Ratio |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 40 mg | Ratio of AUCt,ss/AUCt (RAAUC) | Regorafenib (n=3,5,6,2,3,0,1,5) | 3.78 Ratio |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 100 mg | Ratio of AUCt,ss/AUCt (RAAUC) | M5 (BAY81-8752) (n=0,4,,6,2,3,0,1,5) | 41.2 Ratio |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 100 mg | Ratio of AUCt,ss/AUCt (RAAUC) | Regorafenib (n=3,5,6,2,3,0,1,5) | 3.15 Ratio |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 100 mg | Ratio of AUCt,ss/AUCt (RAAUC) | M2 (BAY75-7495) (n=3,5,6,2,3,0,1,5) | 4.63 Ratio |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 120 mg | Ratio of AUCt,ss/AUCt (RAAUC) | Regorafenib (n=3,5,6,2,3,0,1,5) | 1.37 Ratio |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 120 mg | Ratio of AUCt,ss/AUCt (RAAUC) | M2 (BAY75-7495) (n=3,5,6,2,3,0,1,5) | 2.71 Ratio |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 120 mg | Ratio of AUCt,ss/AUCt (RAAUC) | M5 (BAY81-8752) (n=0,4,,6,2,3,0,1,5) | 34.7 Ratio |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 140 mg | Ratio of AUCt,ss/AUCt (RAAUC) | M2 (BAY75-7495) (n=3,5,6,2,3,0,1,5) | 3.60 Ratio |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 140 mg | Ratio of AUCt,ss/AUCt (RAAUC) | Regorafenib (n=3,5,6,2,3,0,1,5) | 3.61 Ratio |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 140 mg | Ratio of AUCt,ss/AUCt (RAAUC) | M5 (BAY81-8752) (n=0,4,,6,2,3,0,1,5) | 23.9 Ratio |
| HCC Child-Pugh A Expansion Cohort: Regorafenib 100 mg | Ratio of AUCt,ss/AUCt (RAAUC) | M2 (BAY75-7495) (n=3,5,6,2,3,0,1,5) | NA Ratio |
| HCC Child-Pugh A Expansion Cohort: Regorafenib 100 mg | Ratio of AUCt,ss/AUCt (RAAUC) | Regorafenib (n=3,5,6,2,3,0,1,5) | NA Ratio |
| HCC Child-Pugh A Expansion Cohort: Regorafenib 100 mg | Ratio of AUCt,ss/AUCt (RAAUC) | M5 (BAY81-8752) (n=0,4,,6,2,3,0,1,5) | NA Ratio |
| HCC Child-Pugh B Expansion Cohort: Regorafenib 100 mg | Ratio of AUCt,ss/AUCt (RAAUC) | M2 (BAY75-7495) (n=3,5,6,2,3,0,1,5) | 4.60 Ratio |
| HCC Child-Pugh B Expansion Cohort: Regorafenib 100 mg | Ratio of AUCt,ss/AUCt (RAAUC) | Regorafenib (n=3,5,6,2,3,0,1,5) | 2.10 Ratio |
| HCC Child-Pugh B Expansion Cohort: Regorafenib 100 mg | Ratio of AUCt,ss/AUCt (RAAUC) | M5 (BAY81-8752) (n=0,4,,6,2,3,0,1,5) | 63.0 Ratio |
| NSCLC Expansion Cohort: Regorafenib 100 mg | Ratio of AUCt,ss/AUCt (RAAUC) | Regorafenib (n=3,5,6,2,3,0,1,5) | 2.67 Ratio |
| NSCLC Expansion Cohort: Regorafenib 100 mg | Ratio of AUCt,ss/AUCt (RAAUC) | M2 (BAY75-7495) (n=3,5,6,2,3,0,1,5) | 2.74 Ratio |
| NSCLC Expansion Cohort: Regorafenib 100 mg | Ratio of AUCt,ss/AUCt (RAAUC) | M5 (BAY81-8752) (n=0,4,,6,2,3,0,1,5) | 18.5 Ratio |
Secondary
Ratio of Cmax,ss/Cmax (RACmax)
RACmax is the ratio of the highest drug concentration at steady state to the highest drug concentration after single dose administration. It is obtained by collecting a series of blood samples at various times after dosing, and measuring them for drug content.
Time frame: Blood samples were collected on Cycle 1, Day 1 and Cycle 2, Day 1 and on Cycle 3, Day 1 for expansion cohort. Samples were drawn at the following time points: 0 h pre-dose, 0.5, 1, 2, 4, 8, 10 and 24h post-dose
Population: Pharmacokinetic population; Number of Participants with an evaluable Cmax,ss and Cmax in at least one analyte were 1 (M5) in 20mg; 5 (regorafenib and M2) and 4 (M5) in 40mg; 6 in 100 mg; 2 in 120 mg; 3 in 140 mg; 0 in HCC Child Pugh A; 1 in HCC Child Pugh B; 5 in NSCLC
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Regorafenib, 20 mg, 40 mg, 100 mg, 120 mg, 140 mg | Ratio of Cmax,ss/Cmax (RACmax) | Regorafenib (n=3,5,6,2,3,0,1,5) | 3.78 Ratio |
| Regorafenib, 20 mg, 40 mg, 100 mg, 120 mg, 140 mg | Ratio of Cmax,ss/Cmax (RACmax) | M5 (BAY81-8752) (n=1,4,6,2,3,0,1,5) | 3.80 Ratio |
| Regorafenib, 20 mg, 40 mg, 100 mg, 120 mg, 140 mg | Ratio of Cmax,ss/Cmax (RACmax) | M2 (BAY75-7495) (n=3,5,6,2,3,0,1,5) | 4.86 Ratio |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 40 mg | Ratio of Cmax,ss/Cmax (RACmax) | M5 (BAY81-8752) (n=1,4,6,2,3,0,1,5) | 22.8 Ratio |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 40 mg | Ratio of Cmax,ss/Cmax (RACmax) | M2 (BAY75-7495) (n=3,5,6,2,3,0,1,5) | 4.26 Ratio |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 40 mg | Ratio of Cmax,ss/Cmax (RACmax) | Regorafenib (n=3,5,6,2,3,0,1,5) | 3.34 Ratio |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 100 mg | Ratio of Cmax,ss/Cmax (RACmax) | M5 (BAY81-8752) (n=1,4,6,2,3,0,1,5) | 32.5 Ratio |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 100 mg | Ratio of Cmax,ss/Cmax (RACmax) | Regorafenib (n=3,5,6,2,3,0,1,5) | 3.50 Ratio |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 100 mg | Ratio of Cmax,ss/Cmax (RACmax) | M2 (BAY75-7495) (n=3,5,6,2,3,0,1,5) | 5.39 Ratio |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 120 mg | Ratio of Cmax,ss/Cmax (RACmax) | Regorafenib (n=3,5,6,2,3,0,1,5) | 1.53 Ratio |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 120 mg | Ratio of Cmax,ss/Cmax (RACmax) | M2 (BAY75-7495) (n=3,5,6,2,3,0,1,5) | 3.06 Ratio |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 120 mg | Ratio of Cmax,ss/Cmax (RACmax) | M5 (BAY81-8752) (n=1,4,6,2,3,0,1,5) | 39.3 Ratio |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 140 mg | Ratio of Cmax,ss/Cmax (RACmax) | M2 (BAY75-7495) (n=3,5,6,2,3,0,1,5) | 3.33 Ratio |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 140 mg | Ratio of Cmax,ss/Cmax (RACmax) | Regorafenib (n=3,5,6,2,3,0,1,5) | 2.84 Ratio |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 140 mg | Ratio of Cmax,ss/Cmax (RACmax) | M5 (BAY81-8752) (n=1,4,6,2,3,0,1,5) | 18.9 Ratio |
| HCC Child-Pugh A Expansion Cohort: Regorafenib 100 mg | Ratio of Cmax,ss/Cmax (RACmax) | M2 (BAY75-7495) (n=3,5,6,2,3,0,1,5) | NA Ratio |
| HCC Child-Pugh A Expansion Cohort: Regorafenib 100 mg | Ratio of Cmax,ss/Cmax (RACmax) | Regorafenib (n=3,5,6,2,3,0,1,5) | NA Ratio |
| HCC Child-Pugh A Expansion Cohort: Regorafenib 100 mg | Ratio of Cmax,ss/Cmax (RACmax) | M5 (BAY81-8752) (n=1,4,6,2,3,0,1,5) | NA Ratio |
| HCC Child-Pugh B Expansion Cohort: Regorafenib 100 mg | Ratio of Cmax,ss/Cmax (RACmax) | M2 (BAY75-7495) (n=3,5,6,2,3,0,1,5) | 3.40 Ratio |
| HCC Child-Pugh B Expansion Cohort: Regorafenib 100 mg | Ratio of Cmax,ss/Cmax (RACmax) | Regorafenib (n=3,5,6,2,3,0,1,5) | 1.90 Ratio |
| HCC Child-Pugh B Expansion Cohort: Regorafenib 100 mg | Ratio of Cmax,ss/Cmax (RACmax) | M5 (BAY81-8752) (n=1,4,6,2,3,0,1,5) | 45.0 Ratio |
| NSCLC Expansion Cohort: Regorafenib 100 mg | Ratio of Cmax,ss/Cmax (RACmax) | Regorafenib (n=3,5,6,2,3,0,1,5) | 1.82 Ratio |
| NSCLC Expansion Cohort: Regorafenib 100 mg | Ratio of Cmax,ss/Cmax (RACmax) | M2 (BAY75-7495) (n=3,5,6,2,3,0,1,5) | 1.83 Ratio |
| NSCLC Expansion Cohort: Regorafenib 100 mg | Ratio of Cmax,ss/Cmax (RACmax) | M5 (BAY81-8752) (n=1,4,6,2,3,0,1,5) | 11.9 Ratio |
Secondary
Ratio of Cmin,ss/Cmin (RACmin)
RACmin is the ratio of the lowest drug concentration at steady state to the lowest drug concentration after single dose administration. It is obtained by collecting a series of blood samples at various times after dosing, and measuring them for drug content.
Time frame: Blood samples were collected on Cycle 1, Day 1 and Cycle 2, Day 1 and on Cycle 3, Day 1 for expansion cohort. Samples were drawn at the following time points: 0 h pre-dose, 0.5, 1, 2, 4, 8, 10 and 24h post-dose
Population: Pharmacokinetic population; Number of Participants with an evaluable Cmin,ss and Cmin in at least one analyte were 0 (M5) in 20mg; 6 (regorafenib and M2) and 4 (M5) in 40mg; 6 in 100 mg; 2 in 120 mg; 3 in 140 mg; 0 in HCC Child Pugh A; 1 in HCC Child Pugh B; 5 in NSCLC
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Regorafenib, 20 mg, 40 mg, 100 mg, 120 mg, 140 mg | Ratio of Cmin,ss/Cmin (RACmin) | Regorafenib (n=3,6,6,2,3,0,1,5) | 4.82 Ratio |
| Regorafenib, 20 mg, 40 mg, 100 mg, 120 mg, 140 mg | Ratio of Cmin,ss/Cmin (RACmin) | M5 (BAY81-8752) (n=0,4,,6,2,3,0,1,5) | NA Ratio |
| Regorafenib, 20 mg, 40 mg, 100 mg, 120 mg, 140 mg | Ratio of Cmin,ss/Cmin (RACmin) | M2 (BAY75-7495) (n=3,6,6,2,3,0,1,5) | 4.81 Ratio |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 40 mg | Ratio of Cmin,ss/Cmin (RACmin) | M5 (BAY81-8752) (n=0,4,,6,2,3,0,1,5) | 26.1 Ratio |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 40 mg | Ratio of Cmin,ss/Cmin (RACmin) | M2 (BAY75-7495) (n=3,6,6,2,3,0,1,5) | 10.4 Ratio |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 40 mg | Ratio of Cmin,ss/Cmin (RACmin) | Regorafenib (n=3,6,6,2,3,0,1,5) | 34.9 Ratio |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 100 mg | Ratio of Cmin,ss/Cmin (RACmin) | M5 (BAY81-8752) (n=0,4,,6,2,3,0,1,5) | 102 Ratio |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 100 mg | Ratio of Cmin,ss/Cmin (RACmin) | Regorafenib (n=3,6,6,2,3,0,1,5) | 26.1 Ratio |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 100 mg | Ratio of Cmin,ss/Cmin (RACmin) | M2 (BAY75-7495) (n=3,6,6,2,3,0,1,5) | 24.2 Ratio |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 120 mg | Ratio of Cmin,ss/Cmin (RACmin) | Regorafenib (n=3,6,6,2,3,0,1,5) | 413 Ratio |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 120 mg | Ratio of Cmin,ss/Cmin (RACmin) | M2 (BAY75-7495) (n=3,6,6,2,3,0,1,5) | 12.6 Ratio |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 120 mg | Ratio of Cmin,ss/Cmin (RACmin) | M5 (BAY81-8752) (n=0,4,,6,2,3,0,1,5) | 335 Ratio |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 140 mg | Ratio of Cmin,ss/Cmin (RACmin) | M2 (BAY75-7495) (n=3,6,6,2,3,0,1,5) | 3.33 Ratio |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 140 mg | Ratio of Cmin,ss/Cmin (RACmin) | Regorafenib (n=3,6,6,2,3,0,1,5) | 10.9 Ratio |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 140 mg | Ratio of Cmin,ss/Cmin (RACmin) | M5 (BAY81-8752) (n=0,4,,6,2,3,0,1,5) | 46.2 Ratio |
| HCC Child-Pugh A Expansion Cohort: Regorafenib 100 mg | Ratio of Cmin,ss/Cmin (RACmin) | M2 (BAY75-7495) (n=3,6,6,2,3,0,1,5) | NA Ratio |
| HCC Child-Pugh A Expansion Cohort: Regorafenib 100 mg | Ratio of Cmin,ss/Cmin (RACmin) | Regorafenib (n=3,6,6,2,3,0,1,5) | NA Ratio |
| HCC Child-Pugh A Expansion Cohort: Regorafenib 100 mg | Ratio of Cmin,ss/Cmin (RACmin) | M5 (BAY81-8752) (n=0,4,,6,2,3,0,1,5) | NA Ratio |
| HCC Child-Pugh B Expansion Cohort: Regorafenib 100 mg | Ratio of Cmin,ss/Cmin (RACmin) | M2 (BAY75-7495) (n=3,6,6,2,3,0,1,5) | 103 Ratio |
| HCC Child-Pugh B Expansion Cohort: Regorafenib 100 mg | Ratio of Cmin,ss/Cmin (RACmin) | Regorafenib (n=3,6,6,2,3,0,1,5) | 7.80 Ratio |
| HCC Child-Pugh B Expansion Cohort: Regorafenib 100 mg | Ratio of Cmin,ss/Cmin (RACmin) | M5 (BAY81-8752) (n=0,4,,6,2,3,0,1,5) | 257 Ratio |
| NSCLC Expansion Cohort: Regorafenib 100 mg | Ratio of Cmin,ss/Cmin (RACmin) | Regorafenib (n=3,6,6,2,3,0,1,5) | 14.1 Ratio |
| NSCLC Expansion Cohort: Regorafenib 100 mg | Ratio of Cmin,ss/Cmin (RACmin) | M2 (BAY75-7495) (n=3,6,6,2,3,0,1,5) | 11.5 Ratio |
| NSCLC Expansion Cohort: Regorafenib 100 mg | Ratio of Cmin,ss/Cmin (RACmin) | M5 (BAY81-8752) (n=0,4,,6,2,3,0,1,5) | 22.4 Ratio |
Secondary
Time to Reach Maximum Observed Plasma Concentration at Steady State (Tmax,ss)
Tmax,ss refers to the time after multiple dose administration and after a steady state concentration has been reached when a drug attains its highest measurable concentration (Cmax). It is obtained by collecting a series of blood samples at various times after dosing, and measuring them for drug content.
Time frame: Blood samples were collected on Cycle 2, Day 1 and on Cycle 3, Day 1 for expansion cohort. Samples were drawn at the following time points: 0 h pre-dose, 0.5, 1, 2, 4, 8, 10 and 24h post-dose
Population: Pharmacokinetic population; Number of Participants with an evaluable Tmax,ss in at least one analyte were 6 in 40mg; 6 in 100 mg; 2 in 120 mg; 3 in 140 mg; 0 in HCC Child Pugh A; 1 in HCC Child Pugh B; 5 in NSCLC
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Regorafenib, 20 mg, 40 mg, 100 mg, 120 mg, 140 mg | Time to Reach Maximum Observed Plasma Concentration at Steady State (Tmax,ss) | Regorafenib (n=3,6,6,2,3,0,1,5) | 2.00 h |
| Regorafenib, 20 mg, 40 mg, 100 mg, 120 mg, 140 mg | Time to Reach Maximum Observed Plasma Concentration at Steady State (Tmax,ss) | M5 (BAY81-8752) (n=3,6,6,2,3,0,1,5) | 2.00 h |
| Regorafenib, 20 mg, 40 mg, 100 mg, 120 mg, 140 mg | Time to Reach Maximum Observed Plasma Concentration at Steady State (Tmax,ss) | M2 (BAY75-7495) (n=3,6,6,2,3,0,1,5) | 2.00 h |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 40 mg | Time to Reach Maximum Observed Plasma Concentration at Steady State (Tmax,ss) | M5 (BAY81-8752) (n=3,6,6,2,3,0,1,5) | 1.00 h |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 40 mg | Time to Reach Maximum Observed Plasma Concentration at Steady State (Tmax,ss) | M2 (BAY75-7495) (n=3,6,6,2,3,0,1,5) | 1.50 h |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 40 mg | Time to Reach Maximum Observed Plasma Concentration at Steady State (Tmax,ss) | Regorafenib (n=3,6,6,2,3,0,1,5) | 2.00 h |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 100 mg | Time to Reach Maximum Observed Plasma Concentration at Steady State (Tmax,ss) | M5 (BAY81-8752) (n=3,6,6,2,3,0,1,5) | 1.00 h |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 100 mg | Time to Reach Maximum Observed Plasma Concentration at Steady State (Tmax,ss) | Regorafenib (n=3,6,6,2,3,0,1,5) | 1.25 h |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 100 mg | Time to Reach Maximum Observed Plasma Concentration at Steady State (Tmax,ss) | M2 (BAY75-7495) (n=3,6,6,2,3,0,1,5) | 2.00 h |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 120 mg | Time to Reach Maximum Observed Plasma Concentration at Steady State (Tmax,ss) | Regorafenib (n=3,6,6,2,3,0,1,5) | 2.00 h |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 120 mg | Time to Reach Maximum Observed Plasma Concentration at Steady State (Tmax,ss) | M2 (BAY75-7495) (n=3,6,6,2,3,0,1,5) | 2.00 h |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 120 mg | Time to Reach Maximum Observed Plasma Concentration at Steady State (Tmax,ss) | M5 (BAY81-8752) (n=3,6,6,2,3,0,1,5) | 1.50 h |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 140 mg | Time to Reach Maximum Observed Plasma Concentration at Steady State (Tmax,ss) | M2 (BAY75-7495) (n=3,6,6,2,3,0,1,5) | 2.00 h |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 140 mg | Time to Reach Maximum Observed Plasma Concentration at Steady State (Tmax,ss) | Regorafenib (n=3,6,6,2,3,0,1,5) | 2.00 h |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 140 mg | Time to Reach Maximum Observed Plasma Concentration at Steady State (Tmax,ss) | M5 (BAY81-8752) (n=3,6,6,2,3,0,1,5) | 1.00 h |
| HCC Child-Pugh A Expansion Cohort: Regorafenib 100 mg | Time to Reach Maximum Observed Plasma Concentration at Steady State (Tmax,ss) | M2 (BAY75-7495) (n=3,6,6,2,3,0,1,5) | NA h |
| HCC Child-Pugh A Expansion Cohort: Regorafenib 100 mg | Time to Reach Maximum Observed Plasma Concentration at Steady State (Tmax,ss) | Regorafenib (n=3,6,6,2,3,0,1,5) | NA h |
| HCC Child-Pugh A Expansion Cohort: Regorafenib 100 mg | Time to Reach Maximum Observed Plasma Concentration at Steady State (Tmax,ss) | M5 (BAY81-8752) (n=3,6,6,2,3,0,1,5) | NA h |
| HCC Child-Pugh B Expansion Cohort: Regorafenib 100 mg | Time to Reach Maximum Observed Plasma Concentration at Steady State (Tmax,ss) | M2 (BAY75-7495) (n=3,6,6,2,3,0,1,5) | 10.0 h |
| HCC Child-Pugh B Expansion Cohort: Regorafenib 100 mg | Time to Reach Maximum Observed Plasma Concentration at Steady State (Tmax,ss) | Regorafenib (n=3,6,6,2,3,0,1,5) | 4.03 h |
| HCC Child-Pugh B Expansion Cohort: Regorafenib 100 mg | Time to Reach Maximum Observed Plasma Concentration at Steady State (Tmax,ss) | M5 (BAY81-8752) (n=3,6,6,2,3,0,1,5) | 0.00 h |
| NSCLC Expansion Cohort: Regorafenib 100 mg | Time to Reach Maximum Observed Plasma Concentration at Steady State (Tmax,ss) | Regorafenib (n=3,6,6,2,3,0,1,5) | 4.00 h |
| NSCLC Expansion Cohort: Regorafenib 100 mg | Time to Reach Maximum Observed Plasma Concentration at Steady State (Tmax,ss) | M2 (BAY75-7495) (n=3,6,6,2,3,0,1,5) | 4.00 h |
| NSCLC Expansion Cohort: Regorafenib 100 mg | Time to Reach Maximum Observed Plasma Concentration at Steady State (Tmax,ss) | M5 (BAY81-8752) (n=3,6,6,2,3,0,1,5) | 4.00 h |
Secondary
Time to Reach Maximum Observed Plasma Concentration (Tmax)
Tmax refers to the time after dosing when a drug attains its highest measurable concentration (Cmax). It is obtained by collecting a series of blood samples at various times after dosing, and measuring them for drug content.
Time frame: Blood samples were collected on Cycle 1, Day 1. Samples were drawn at the following time points: 0 h pre-dose, 0.5, 1, 2, 4, 8, 10, 24, and 48 h post-dose.
Population: Pharmacokinetic population; Number of Participants with an evaluable Tmax in at least one analyte were 1 (M-5) in 20 mg; 5 (M-5) in 40mg; 13 (M-5) in HCC Child Pugh A; 22 (M-5) in NSCLC
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Regorafenib, 20 mg, 40 mg, 100 mg, 120 mg, 140 mg | Time to Reach Maximum Observed Plasma Concentration (Tmax) | Regorafenib (n=3,8,10,6,10,14,4,24) | 8.00 h |
| Regorafenib, 20 mg, 40 mg, 100 mg, 120 mg, 140 mg | Time to Reach Maximum Observed Plasma Concentration (Tmax) | M5 (BAY81-8752) (n=1,5,10,6,10,13,4,22) | 48.0 h |
| Regorafenib, 20 mg, 40 mg, 100 mg, 120 mg, 140 mg | Time to Reach Maximum Observed Plasma Concentration (Tmax) | M2 (BAY75-7495) (n=3,8,10,6,10,14,4,24) | 8.00 h |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 40 mg | Time to Reach Maximum Observed Plasma Concentration (Tmax) | M5 (BAY81-8752) (n=1,5,10,6,10,13,4,22) | 47.8 h |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 40 mg | Time to Reach Maximum Observed Plasma Concentration (Tmax) | M2 (BAY75-7495) (n=3,8,10,6,10,14,4,24) | 2.02 h |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 40 mg | Time to Reach Maximum Observed Plasma Concentration (Tmax) | Regorafenib (n=3,8,10,6,10,14,4,24) | 2.02 h |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 100 mg | Time to Reach Maximum Observed Plasma Concentration (Tmax) | M5 (BAY81-8752) (n=1,5,10,6,10,13,4,22) | 48.0 h |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 100 mg | Time to Reach Maximum Observed Plasma Concentration (Tmax) | Regorafenib (n=3,8,10,6,10,14,4,24) | 5.00 h |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 100 mg | Time to Reach Maximum Observed Plasma Concentration (Tmax) | M2 (BAY75-7495) (n=3,8,10,6,10,14,4,24) | 10.0 h |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 120 mg | Time to Reach Maximum Observed Plasma Concentration (Tmax) | Regorafenib (n=3,8,10,6,10,14,4,24) | 6.00 h |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 120 mg | Time to Reach Maximum Observed Plasma Concentration (Tmax) | M2 (BAY75-7495) (n=3,8,10,6,10,14,4,24) | 9.00 h |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 120 mg | Time to Reach Maximum Observed Plasma Concentration (Tmax) | M5 (BAY81-8752) (n=1,5,10,6,10,13,4,22) | 24.6 h |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 140 mg | Time to Reach Maximum Observed Plasma Concentration (Tmax) | M2 (BAY75-7495) (n=3,8,10,6,10,14,4,24) | 4.00 h |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 140 mg | Time to Reach Maximum Observed Plasma Concentration (Tmax) | Regorafenib (n=3,8,10,6,10,14,4,24) | 3.01 h |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 140 mg | Time to Reach Maximum Observed Plasma Concentration (Tmax) | M5 (BAY81-8752) (n=1,5,10,6,10,13,4,22) | 47.6 h |
| HCC Child-Pugh A Expansion Cohort: Regorafenib 100 mg | Time to Reach Maximum Observed Plasma Concentration (Tmax) | M2 (BAY75-7495) (n=3,8,10,6,10,14,4,24) | 3.01 h |
| HCC Child-Pugh A Expansion Cohort: Regorafenib 100 mg | Time to Reach Maximum Observed Plasma Concentration (Tmax) | Regorafenib (n=3,8,10,6,10,14,4,24) | 3.03 h |
| HCC Child-Pugh A Expansion Cohort: Regorafenib 100 mg | Time to Reach Maximum Observed Plasma Concentration (Tmax) | M5 (BAY81-8752) (n=1,5,10,6,10,13,4,22) | 46.8 h |
| HCC Child-Pugh B Expansion Cohort: Regorafenib 100 mg | Time to Reach Maximum Observed Plasma Concentration (Tmax) | M2 (BAY75-7495) (n=3,8,10,6,10,14,4,24) | 10.0 h |
| HCC Child-Pugh B Expansion Cohort: Regorafenib 100 mg | Time to Reach Maximum Observed Plasma Concentration (Tmax) | Regorafenib (n=3,8,10,6,10,14,4,24) | 3.00 h |
| HCC Child-Pugh B Expansion Cohort: Regorafenib 100 mg | Time to Reach Maximum Observed Plasma Concentration (Tmax) | M5 (BAY81-8752) (n=1,5,10,6,10,13,4,22) | 34.9 h |
| NSCLC Expansion Cohort: Regorafenib 100 mg | Time to Reach Maximum Observed Plasma Concentration (Tmax) | Regorafenib (n=3,8,10,6,10,14,4,24) | 2.00 h |
| NSCLC Expansion Cohort: Regorafenib 100 mg | Time to Reach Maximum Observed Plasma Concentration (Tmax) | M2 (BAY75-7495) (n=3,8,10,6,10,14,4,24) | 2.01 h |
| NSCLC Expansion Cohort: Regorafenib 100 mg | Time to Reach Maximum Observed Plasma Concentration (Tmax) | M5 (BAY81-8752) (n=1,5,10,6,10,13,4,22) | 47.8 h |
Other Pre-specified
Tumor Progression in Dose Escalation Cohort
Tumor progression evaluates changes in a tumor or tumors over time due to worsening of disease. Measurements and observations of the tumor status were performed before, during and after treatment. Progression for solid tumors was evaluated based on the Response Evaluation Criteria in Solid Tumors (RECIST 1.0) criteria. Tumor dimensions were measured in millimeters and the longest diameter (LD) was recorded for up to 5 lesions per organ and 10 lesions total. A sum of the LD for all target lesions was recorded. The use of a 20% increase in the sum of LD of target lesions from the smallest sum or appearance of a new lesion was assessed as progression of disease.
Time frame: From the screening visit of the first participant until the last evaluation of the final participant over 6 years later, assessed at the screening visit, end of cycle 2, end of each even cycle and during the final visit (end of treatment)
Population: Intent-to-treat (ITT) efficacy analysis (set)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Regorafenib, 20 mg, 40 mg, 100 mg, 120 mg, 140 mg | Tumor Progression in Dose Escalation Cohort | Participants without progression | 1 Participants |
| Regorafenib, 20 mg, 40 mg, 100 mg, 120 mg, 140 mg | Tumor Progression in Dose Escalation Cohort | Participants with progression | 2 Participants |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 40 mg | Tumor Progression in Dose Escalation Cohort | Participants with progression | 5 Participants |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 40 mg | Tumor Progression in Dose Escalation Cohort | Participants without progression | 3 Participants |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 100 mg | Tumor Progression in Dose Escalation Cohort | Participants without progression | 9 Participants |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 100 mg | Tumor Progression in Dose Escalation Cohort | Participants with progression | 2 Participants |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 120 mg | Tumor Progression in Dose Escalation Cohort | Participants without progression | 2 Participants |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 120 mg | Tumor Progression in Dose Escalation Cohort | Participants with progression | 3 Participants |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 140 mg | Tumor Progression in Dose Escalation Cohort | Participants with progression | 5 Participants |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 140 mg | Tumor Progression in Dose Escalation Cohort | Participants without progression | 5 Participants |
Other Pre-specified
Tumor Progression in Expansion Cohort
Tumor progression evaluates changes in a tumor or tumors over time due to worsening of disease. Measurements and observations of the tumor status were performed before, during and after treatment. Tumor progression evaluates changes in a tumor or tumors over time due to worsening of disease. Measurements and observations of the tumor status were performed before, during and after treatment. Progression for solid tumors was evaluated based on the Response Evaluation Criteria in Solid Tumors (RECIST 1.0) criteria. Tumor dimensions were measured in millimeters and the longest diameter (LD) was recorded for up to 5 lesions per organ and 10 lesions total. A sum of the LD for all target lesions was recorded. The use of a 20% increase in the sum of LD of target lesions from the smallest sum or appearance of a new lesion was assessed as progression of disease.
Time frame: From the screening visit of the first participant until the last evaluation of the final participant over 6 years later, assessed at the screening visit, end of cycle 2, end of each even cycle and during the final visit (end of treatment)
Population: ITT efficacy analysis (set), expansion cohorts only
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Regorafenib, 20 mg, 40 mg, 100 mg, 120 mg, 140 mg | Tumor Progression in Expansion Cohort | Participants without progression | 10 Participants |
| Regorafenib, 20 mg, 40 mg, 100 mg, 120 mg, 140 mg | Tumor Progression in Expansion Cohort | Participants with progression | 12 Participants |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 40 mg | Tumor Progression in Expansion Cohort | Participants without progression | 6 Participants |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 40 mg | Tumor Progression in Expansion Cohort | Participants with progression | 16 Participants |
Other Pre-specified
Tumor Response in Dose Escalation Cohort
Tumor Response (= Best Overall Response) of a participant was defined as the best tumor response (Complete Response (CR), Partial Response (PR), Stable Disease (SD), or Progressive Disease (PD)) observed during trial period assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. CR was defined as disappearance of tumor lesions, PR was defined as a decrease of at least 30% in the sum of tumor lesion sizes, SD was defined as steady state of disease, PD was defined as an increase of at least 20% in the sum of tumor lesions sizes.
Time frame: From the screening visit of the first participant until the last evaluation of the final participant over 6 years later, assessed at the screening visit, end of cycle 2, end of each even cycle and during the final visit (end of treatment)
Population: ITT efficacy analysis (set)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Regorafenib, 20 mg, 40 mg, 100 mg, 120 mg, 140 mg | Tumor Response in Dose Escalation Cohort | Progressive Disease (PD) | 2 Participants |
| Regorafenib, 20 mg, 40 mg, 100 mg, 120 mg, 140 mg | Tumor Response in Dose Escalation Cohort | Not assessable | 0 Participants |
| Regorafenib, 20 mg, 40 mg, 100 mg, 120 mg, 140 mg | Tumor Response in Dose Escalation Cohort | Progression | 0 Participants |
| Regorafenib, 20 mg, 40 mg, 100 mg, 120 mg, 140 mg | Tumor Response in Dose Escalation Cohort | Partial Response (PR) | 0 Participants |
| Regorafenib, 20 mg, 40 mg, 100 mg, 120 mg, 140 mg | Tumor Response in Dose Escalation Cohort | Stable Disease (SD) | 1 Participants |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 40 mg | Tumor Response in Dose Escalation Cohort | Progressive Disease (PD) | 4 Participants |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 40 mg | Tumor Response in Dose Escalation Cohort | Stable Disease (SD) | 2 Participants |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 40 mg | Tumor Response in Dose Escalation Cohort | Partial Response (PR) | 0 Participants |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 40 mg | Tumor Response in Dose Escalation Cohort | Progression | 1 Participants |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 40 mg | Tumor Response in Dose Escalation Cohort | Not assessable | 1 Participants |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 100 mg | Tumor Response in Dose Escalation Cohort | Stable Disease (SD) | 5 Participants |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 100 mg | Tumor Response in Dose Escalation Cohort | Not assessable | 2 Participants |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 100 mg | Tumor Response in Dose Escalation Cohort | Partial Response (PR) | 2 Participants |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 100 mg | Tumor Response in Dose Escalation Cohort | Progressive Disease (PD) | 2 Participants |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 100 mg | Tumor Response in Dose Escalation Cohort | Progression | 0 Participants |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 120 mg | Tumor Response in Dose Escalation Cohort | Progression | 1 Participants |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 120 mg | Tumor Response in Dose Escalation Cohort | Not assessable | 0 Participants |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 120 mg | Tumor Response in Dose Escalation Cohort | Progressive Disease (PD) | 2 Participants |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 120 mg | Tumor Response in Dose Escalation Cohort | Stable Disease (SD) | 2 Participants |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 120 mg | Tumor Response in Dose Escalation Cohort | Partial Response (PR) | 0 Participants |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 140 mg | Tumor Response in Dose Escalation Cohort | Stable Disease (SD) | 4 Participants |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 140 mg | Tumor Response in Dose Escalation Cohort | Progressive Disease (PD) | 4 Participants |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 140 mg | Tumor Response in Dose Escalation Cohort | Not assessable | 0 Participants |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 140 mg | Tumor Response in Dose Escalation Cohort | Progression | 1 Participants |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 140 mg | Tumor Response in Dose Escalation Cohort | Partial Response (PR) | 1 Participants |
Other Pre-specified
Tumor Response in Expansion Cohort
Tumor Response (= Best Overall Response) of a participant was defined as the best tumor response (Complete Response (CR), Partial Response (PR), Stable Disease (SD), or Progressive Disease (PD)) observed during trial period assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. CR was defined as disappearance of tumor lesions, PR was defined as a decrease of at least 30% in the sum of tumor lesion sizes, SD was defined as steady state of disease, PD was defined as an increase of at least 20% in the sum of tumor lesions sizes.
Time frame: From the screening visit of the first participant until the last evaluation of the final participant over 6 years later, assessed at the screening visit, end of cycle 2, end of each even cycle and during the final visit (end of treatment)
Population: ITT efficacy analysis (set), expansion cohorts only
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Regorafenib, 20 mg, 40 mg, 100 mg, 120 mg, 140 mg | Tumor Response in Expansion Cohort | Progression | 2 Participants |
| Regorafenib, 20 mg, 40 mg, 100 mg, 120 mg, 140 mg | Tumor Response in Expansion Cohort | Partial Response (PR) | 1 Participants |
| Regorafenib, 20 mg, 40 mg, 100 mg, 120 mg, 140 mg | Tumor Response in Expansion Cohort | Not assessable | 3 Participants |
| Regorafenib, 20 mg, 40 mg, 100 mg, 120 mg, 140 mg | Tumor Response in Expansion Cohort | Stable Disease (SD) | 6 Participants |
| Regorafenib, 20 mg, 40 mg, 100 mg, 120 mg, 140 mg | Tumor Response in Expansion Cohort | Progressive Disease (PD) | 10 Participants |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 40 mg | Tumor Response in Expansion Cohort | Stable Disease (SD) | 5 Participants |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 40 mg | Tumor Response in Expansion Cohort | Progressive Disease (PD) | 12 Participants |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 40 mg | Tumor Response in Expansion Cohort | Progression | 4 Participants |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 40 mg | Tumor Response in Expansion Cohort | Not assessable | 1 Participants |
| Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 40 mg | Tumor Response in Expansion Cohort | Partial Response (PR) | 0 Participants |