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.

Escalation cohort: Regorafenib (Stivarga, BAY73-4506) 20 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.

Escalation cohort: Regorafenib (Stivarga, BAY73-4506) 40 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.

Escalation cohort: Regorafenib (Stivarga, BAY73-4506) 100 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.

Escalation cohort: Regorafenib (Stivarga, BAY73-4506) 120 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.

Escalation cohort: Regorafenib (Stivarga, BAY73-4506) 140 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.

HCC Child-Pugh A 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.

HCC Child-Pugh B 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.

NSCLC expansion cohort: Regorafenib 100 mg

Bayer Study Director

Continuous dosing of BAY73-4506 in patients with advanced cancer

Continuous Dosing of BAY73-4506 in Patients With Advanced Malignancies

Open Label, Phase I Study to Determine the Safety, Tolerability, Maximum Tolerated Dose, Pharmacokinetics, and Biomarker Status of BAY73-4506 in Patients With Advanced Malignancies

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 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 (= 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.

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).

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.

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,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(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.

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.

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.

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.

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.

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,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(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.

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.

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.

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.

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.

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.

The analysis of Biomarker VEGF plasma levels is not done

The analysis of Biomarker sCEGFR-2 plasma levels is not done.

Bayer

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.

Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 20 mg

Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 40 mg

Participants 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. This arm includes the participants from the dose escalation cohort: Regorafenib 100 mg and the three Expansion Cohorts 'HCC Child-Pugh A Expansion Cohort: Regorafenib 100 mg', 'HCC Child-Pugh B Expansion Cohort: Regorafenib 100 mg', 'NSCLC Expansion Cohort: Regorafenib 100 mg'.

Regorafenib (Stivarga, BAY73-4506) 100 mg

Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 120 mg

Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 140 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.

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.

Escalation Cohort: Regorafenib (Stivarga, BAY73-4506) 100 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.

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.

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.

HCC Child-Pugh A 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.

HCC Child-Pugh B Expansion Cohort: Regorafenib 100 mg

NSCLC Expansion Cohort: Regorafenib 100 mg

Total

Age, Continuous

Sex: Female, Male

Therapeutic Area Head

Participants in the dose-escalation cohort received a single 20 mg, 40 mg, 100 mg, 120 mg, 140 mg oral CP tablet of regorafenib respectively 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.

Regorafenib, 20 mg, 40 mg, 100 mg, 120 mg, 140 mg

Safety Population; dose escalation cohorts only

Maximum Tolerated Dose (MTD)

Regorafenib (n=3,7,10,6,10,14,4,24)

M2 (BAY75-7495) (n=3,7,10,6,10,14,4,24)

M5 (BAY81-8752) (n=1,5,10,6,10,13,4,22)

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

Maximum Observed Plasma Concentration After Single Dose Administration (Cmax)

Regorafenib (n=3,5,5,6,6,9,3,19)

M2 (BAY75-7495) (n=3,6,5,3,6,10,2,16)

M5 (BAY81-8752) (n=3,8,10,6,10,1,4,24)

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

Area Under the Concentration vs. Time Curve From Zero to Infinity After Single (First) Dose (AUC)

Regorafenib (n=3,6,6,2,3,0,1,5)

M2 (BAY75-7495) (n=3,6,6,2,3,0,1,5)

M5 (BAY81-8752) (n=3,6,6,2,3,0,1,5)

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

Cmax at Steady State During a Dosing Interval (Cmax,ss)

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

AUC From Time 0 to 24 Hours at Steady State(AUC(0-24),ss)

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

AUC From Time 0 to the Last Data Point > Lower Limit of Quantification (LLOQ) (AUC(0-tlast))

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

Area Under the Concentration vs. Time Curve From Zero to Infinity After Single (First) Dose Divided by Dose (AUC/D)

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

Maximum Observed Plasma Concentration After Single Dose Administration Divided by Dose (Cmax/D)

Regorafenib (n=3,8,10,6,10,14,4,24)

M2 (BAY75-7495) (n=3,8,10,6,10,14,4,24)

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

Time to Reach Maximum Observed Plasma Concentration (Tmax)

Regorafenib (n=3,5,5,3,6,9,22,19)

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

Half-life Associated With the Terminal Slope (T1/2)

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

Cmax at Steady State During a Dosing Interval Divided by Dose (Cmax,ss/D)

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

AUC From Time 0 to 24 Hours at Steady State Divided by Dose (AUC(0-24)ss/D)

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

Time to Reach Maximum Observed Plasma Concentration at Steady State (Tmax,ss)

Regorafenib (n=3,5,6,2,3,0,1,5)

M2 (BAY75-7495) (n=3,5,6,2,3,0,1,5)

M5 (BAY81-8752) (n=1,4,6,2,3,0,1,5)

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

Ratio of Cmax,ss/Cmax (RACmax)

M5 (BAY81-8752) (n=0,4,,6,2,3,0,1,5)

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

Ratio of Cmin,ss/Cmin (RACmin)

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

Ratio of AUCt,ss/AUCt (RAAUC)

Regorafenib (n=0,3,3,2,3,0,1,4)

M2 (BAY75-7495) (n=0,4,3,0,2,0,1,4)

M5 (BAY81-8752) (n=0)

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.

Ratio of AUCt,ss/AUC (RLIN)

Biomarker Vascular Endothelial Growth Factor (VEGF) Plasma Levels

Biomarker Soluble Vascular Endothelial Growth Factor Receptor 2 (sCEGFR-2) Plasma Levels

Participants without progression

Participants with progression

Intent-to-treat (ITT) efficacy analysis (set)

Tumor Progression in Dose Escalation Cohort

Hepatocellular carcinoma (HCC) Participants with Child Pugh A or 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.

HCC Expansion Cohort: Regorafenib 100 mg

ITT efficacy analysis (set), expansion cohorts only

Tumor Progression in Expansion Cohort

Not assessable

Partial Response (PR)

Stable Disease (SD)

Progressive Disease (PD)

Progression

Tumor Response in Dose Escalation Cohort

HCC Expansion Cohort, Regorafenib 100 mg

NSCLC Expansion Cohort, Regorafenib 100 mg

Tumor Response in Expansion Cohort

Participants in the dose-escalation cohort received a single 20 mg oral co-precipitate (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.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Continuous Dosing of BAY73-4506 in Patients With Advanced Malignancies	NCT01117623	Neoplasm	Escalation coho... Escalation coho... Escalation coho... Escalation coho... Escalation coho... HCC Child-Pugh ... HCC Child-Pugh ... NSCLC expansion...	18 Years -	Bayer
Continuous Dosing of BAY73-4506 in Patients With Advanced Malignancies	NCT01117623	Neoplasm	Escalation coho... Escalation coho... Escalation coho... Escalation coho... Escalation coho... HCC Child-Pugh ... HCC Child-Pugh ... NSCLC expansion...	18 Years -	Bayer

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