Continuous Dosing of BAY73-4506 in Patients With Advanced Malignancies

Phase 1CompletedNCT01117623

Bayer86 enrolled

Overview

Continuous dosing of BAY73-4506 in patients with advanced cancer

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Masking

NONE

Enrollment

Conditions

Neoplasm

Interventions

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

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) 40 mgDRUG

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.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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.

Locations (5)

Unnamed facility

Los Angeles, California, United States

Unnamed facility

Aurora, Colorado, United States

Unnamed facility

Houston, Texas, United States

Unnamed facility

San Antonio, Texas, United States

Unnamed facility

Outcomes

Primary Outcomes

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

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

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

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.

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.

Data from ClinicalTrials.gov

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Secondary Outcomes

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

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

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

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.

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.

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.

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

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.

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

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.

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.

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

Biomarker Vascular Endothelial Growth Factor (VEGF) Plasma Levels

The analysis of Biomarker VEGF plasma levels is not done

Time frame: No data obtained

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