Pharmacokinetics and Safety of Regorafenib (BAY73-4506) in Cancer Subjects With Severe Renal Impairment: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Pharmacokinetics and Safety of Regorafenib (BAY73-4506) in Cancer Subjects With Severe Renal Impairment (NCT01853046), a non-randomized phase 1 study. The primary outcome is AUC(0-tlast) [Area Under the Concentration-time Curve After Single (First) Dose From Time Zero to the Last Data Point >LLOQ (Lower Limit of Quantification)] for Regorafenib and Its Pharmacologically Active Metabolites M-2 and M-5.

2. Clinical Question

The study is titled “Pharmacokinetics and Safety of Regorafenib (BAY73-4506) in Cancer Subjects With Severe Renal Impairment.” Its brief summary describes the aim as characterizing pharmacokinetics and safety in subjects with severe renal impairment compared with cancer subjects with normal or mildly impaired renal function. This is a pharmacokinetic and safety question, rather than a randomized test of treatment efficacy.

The primary endpoint concerns exposure after a single first dose. The registry also lists secondary pharmacokinetic outcomes for regorafenib and the metabolites M-2 and M-5, including exposure measures, maximum concentration, time to maximum concentration, terminal half-life, clearance, and apparent volume of distribution. Their outcome values are not reported in the registry record. The record therefore identifies what was intended to be characterized but does not establish the size or precision of any group difference.

3. Trial Design

This was a Phase I, multicenter, non-randomized, open-label, parallel-group study. Its recorded status is completed. The registry lists a start in 2013-06 and primary completion in 2015-07. The sponsor is Bayer, and the condition is Neoplasms. The study was not masked, and allocation was non-randomized.

The parallel groups were defined by renal-function category: normal or mild impairment versus severe impairment. The arm descriptions state that participants received regorafenib 160 mg once daily as a single dose on Day 1 of Stage 1, with a washout of at least 5 days, followed by multiple dosing in an intermittent schedule of 3 week on and 1 week off over 2 cycles in Stage 2 (56 days). The available descriptions are truncated during their account of when Cycle 2 started, so no further detail about that timing can be stated.

Because the groups were not randomized, renal-function category was not assigned by chance. Differences in pharmacokinetic measurements between groups may therefore reflect differences between the groups as well as any relationship between renal function and drug exposure. The registry record does not report group-comparability measures or an adjusted analysis that would address such differences.

The registry lists an enrollment of 24 and three analyses, but the outcome values and detailed analysis results are not reported in the registry record. It also does not report a sample-size justification. The study design and stated aim support describing the trial as a group comparison of pharmacokinetics and safety; they do not, by themselves, supply evidence about the direction or precision of the comparison.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Before assignment: 15 participants (38.5% of 39) were screening failures and 24 participants received treatment with regorafenib. All 15 participants who failed to meet the inclusion and / or exclusion criteria were not assigned to study

Overall Study

Reasons for not completing this period:

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

6. Primary Endpoint

The registry lists the primary outcome as AUC(0-tlast) [Area Under the Concentration-time Curve After Single (First) Dose From Time Zero to the Last Data Point >LLOQ (Lower Limit of Quantification)] for Regorafenib and Its Pharmacologically Active Metabolites M-2 and M-5, measured over Days 1-5: Pre-dose, 0.5, 1, 2, 4, 6, 8, 10, 24, 48 and 96 hours post-dose.

The primary endpoint is AUC(0-tlast) for regorafenib and its pharmacologically active metabolites M-2 and M-5 after the single first dose. The registry defines it as the area under the concentration-time curve from time zero until the last data point above the lower limit of quantification. The unit is mg*h/L. Measurements were scheduled over Days 1-5, including pre-dose and post-dose sampling at 0.5, 1, 2, 4, 6, 8, 10, 24, 48 and 96 hours.

In general, an area under the concentration-time curve combines concentration measurements across time. It is used in pharmacokinetics as a measure of systemic drug exposure, rather than as a direct measure of clinical benefit. AUC(0-tlast) ends at the last measurable concentration, so it is distinct from an estimate that extends exposure beyond the last observed measurable point. The registry describes the endpoint as based on non-compartmental pharmacokinetic evaluation.

The listed summary measure is a geometric mean, with geometric coefficient of variation as the dispersion measure. In general, geometric summaries can be useful for positive pharmacokinetic measurements that vary multiplicatively. The coefficient of variation describes relative variability on the scale used for the geometric summary. The registry record does not report the endpoint values, confidence intervals, or a numerical comparison between the renal-function groups, so the magnitude and precision of exposure differences cannot be assessed from the recorded results.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry identifies AUC(0-tlast) as the primary outcome and describes its summary as a geometric mean with geometric coefficient of variation. It also states that the pharmacokinetic evaluation was non-compartmental. These labels describe the intended measurement and summary, but the registry record does not provide enough outcome results to reproduce or evaluate the analysis.

What does AUC(0-tlast) represent?

In general, pharmacokinetic sampling measures drug concentration in blood at planned times after dosing. An area under the concentration-time curve aggregates those measurements over an interval, reflecting systemic exposure during that interval. Here, the endpoint runs from time zero to the last data point above the lower limit of quantification. Values below that limit are not treated as measurable concentrations for defining the endpoint’s end time. The registry lists sampling from pre-dose through 96 hours after the single first dose over Days 1-5.

The endpoint is reported for regorafenib and the active metabolites M-2 and M-5. These are separate analytes, so each has its own exposure measurement. The registry record does not provide their numerical estimates or any group contrasts. It also does not say how values were handled when an individual’s last measurable sample differed from another individual’s.

What is a non-compartmental evaluation?

In general, non-compartmental pharmacokinetic methods summarize observed concentration-time data without requiring the data to be represented by a specified compartment model. The approach uses measured concentrations and their timing to derive exposure and other pharmacokinetic quantities. The registry names this approach but does not report the detailed calculation procedures, software, handling of missing or below-quantification measurements, or rules for excluding observations.

Why use geometric summaries?

In general, pharmacokinetic exposure measures are positive and can have multiplicative variation. A geometric mean summarizes a distribution on a multiplicative scale, while a geometric coefficient of variation expresses relative spread in that setting. These summaries may make sense for skewed positive measurements, but a reader still needs the estimates and their uncertainty to assess the observed pattern. Those values are not reported in the registry record. A geometric coefficient of variation is not a confidence interval and does not, by itself, quantify uncertainty in a group contrast.

How should a group comparison be assessed?

In general, a comparison should identify the estimate being contrasted and its uncertainty, alongside the analysis population and methods used. A confidence interval describes a range of values compatible with the data and the specified procedure; it helps show precision, not certainty that a particular value is true. A p-value, if reported, addresses compatibility with a statistical null model under the method’s assumptions, rather than the clinical importance of a difference. The registry record does not report a primary endpoint contrast, confidence interval, or p-value.

Because allocation was non-randomized, the groups cannot automatically be interpreted as balanced on other characteristics. In general, adjustment can address measured differences if they are recorded and appropriately modeled, but it cannot guarantee control of unmeasured differences. The registry record does not report whether an adjusted comparison was conducted or which covariates were used. No adjustment procedure should therefore be assumed.

What can be inferred from the reported safety counts?

Counts of participants with events describe observed events during the recorded study period. They do not, on their own, express the time at risk, severity distribution beyond the stated categories, or a causal treatment effect. A comparative safety analysis would need clearly defined event rules, follow-up, and an appropriate analysis plan. The registry provides serious and other adverse-event counts by group but does not report a statistical comparison or the detailed event-collection and analysis methods.

The registry record does not report the statistical analysis plan, missing-data methods, analysis populations, interim analyses, or a sample-size justification. It lists three analyses and 24 outcome measures, but provides no detail in the record to establish how these analyses relate to the primary endpoint. Any planning illustrations based on an observed effect are not observed power and do not substitute for the trial’s own design justification. The record describes planning assumptions of a two-sided significance level of 0.05, equal allocation, and a normal approximation for those illustrations; it does not report the resulting planning figures in the registry record for interpretation.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 24 outcome measures, including a primary pharmacokinetic endpoint and multiple secondary pharmacokinetic outcomes for regorafenib and its metabolites. When many outcomes are examined, the chance of at least one apparently unusual result can increase. In general, multiplicity procedures can control error rates across a defined family of tests, but the appropriate approach depends on the prespecified questions and analysis plan. The registry record does not report a multiplicity strategy, testing hierarchy, or which outcomes were included in any family of comparisons.

The record lists three analyses but does not describe their methods or indicate whether they were prespecified. Interim analyses are not reported in the registry record. No conclusions about interim monitoring or stopping rules can be drawn from that absence of detail.

Missing-data methods and analysis populations are also not reported in the registry record. For a pharmacokinetic endpoint, incomplete concentration-time sampling can affect an individual exposure estimate; in general, the consequences depend on which samples are missing and the rules used to calculate or exclude an estimate. The registry does not state how incomplete profiles, values below the lower limit of quantification, or other unavailable measurements were handled. It does not report the number included in the primary analysis.

The enrollment is listed as 24, but enrollment alone does not establish how many participants contributed evaluable data to each outcome. No sample-size justification is reported. Any planning illustrations described in the record are planning calculations, not observed power or evidence that the analysis was adequately powered. The absent analysis details and primary outcome values limit assessment of both multiplicity and missing-data risks.

11. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: chest pain (16.7%), muscular weakness (16.7%), small intestinal obstruction (11.1%), stress cardiomyopathy (5.6%), intestinal obstruction (5.6%).

The registry reports serious adverse events among 9 of 18 participants at risk in the normal or mild renal impairment group and 2 of 6 participants at risk in the severe renal impairment group. It reports other adverse events among 18 of 18 participants at risk in the normal or mild group and 6 of 6 participants at risk in the severe group. These are descriptive counts recorded for the groups, not estimates from a randomized comparison.

The listed serious-event terms include chest pain and muscular weakness, each reported as 16.7%; small intestinal obstruction, reported as 11.1%; and stress cardiomyopathy, intestinal obstruction, and pancreatitis, each reported as 5.6%. The registry record does not state the denominator basis for these term-specific percentages, so they should not be interpreted as participant risks without that information. The counts for serious adverse events do not indicate the number of events per participant, and the record does not provide event-level timing or duration.

The comparison is limited by non-randomized allocation and the differing group sizes. In general, a count or percentage does not establish that the study drug caused an event or that event frequency differs by renal-function category. The registry does not report a statistical safety comparison. Deaths are not reported in the registry record; this should not be read as confirmation that no deaths occurred.

12. What the Result Does, and Does Not, Mean

This study addresses a focused pharmacokinetic question: whether single-dose exposure to regorafenib and its active metabolites was characterized in cancer subjects with severe renal impairment relative to a normal or mildly impaired renal-function group. Its primary measure, AUC(0-tlast), is intended to summarize systemic exposure through the last measurable concentration. The record also lists other pharmacokinetic outcomes and safety information.

The registry record does not report the primary AUC values, group contrasts, confidence intervals, or p-values. It therefore does not show whether measured exposure was higher, lower, or similar between the groups, or how precisely any comparison was estimated. No statement about the direction or size of an exposure difference can be supported from the record. The absence of posted values is not evidence of no difference.

The study’s non-randomized design also matters. In general, group differences may reflect factors other than renal-function category, and the record does not report adjustments that could address measured differences. The results, if available elsewhere, would need to be considered as an observational group comparison rather than a randomized causal estimate.

These are pharmacokinetic and safety outcomes, not a direct test of clinical efficacy. AUC is a measure of drug exposure, not a measure of tumor response or survival. The serious adverse-event counts and listed terms provide descriptive safety information, but they do not establish causation or comparative safety. The registry does not report a statistical safety comparison, and deaths are not reported in the registry record.

In short, the record establishes the study question, design, dosing stages, and some adverse-event counts. It does not provide the primary pharmacokinetic results needed to judge the exposure comparison, nor enough information to evaluate the analysis methods, precision, or missing-data handling. Any broader claim about clinical outcomes or dosing decisions would go beyond the results recorded.

13. Why This Trial Matters Statistically

Renal function can be relevant to pharmacokinetic questions because a study may need to characterize how drug exposure varies across groups defined by renal status. This trial’s stated purpose was to characterize regorafenib pharmacokinetics and safety in cancer subjects with severe renal impairment compared with subjects with normal or mildly impaired renal function. Its primary endpoint and listed secondary outcomes make the pharmacokinetic focus explicit.

Statistically, the study illustrates the distinction between measuring an exposure quantity and establishing a clinical effect. AUC(0-tlast) summarizes systemic drug exposure over an observed interval; it is not itself a clinical outcome. Careful interpretation therefore depends on the pharmacokinetic estimates, their variability, and their uncertainty, not simply on the endpoint name or the fact that a comparison was planned.

The non-randomized parallel-group design is also important. It permits a descriptive comparison of renal-function groups, but does not ensure that the groups are comparable in other respects. Transparent reporting of baseline characteristics, analysis methods, and uncertainty would help readers assess how much confidence to place in any observed contrast. Those details, along with the primary endpoint values, are not reported in the registry record.

The safety counts show why denominators and event definitions matter. Counts by group are useful descriptive information, but a reader needs the event rules, follow-up context, and analysis approach to interpret comparative safety. The registry also lists serious-event terms with percentages but does not identify their denominator basis. The study is therefore statistically informative as an example of a focused pharmacokinetic design, while the posted record leaves key result and analysis details unavailable for judging the exposure comparison.

14. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The most direct limitation is that the primary endpoint results are not reported in the registry record. No group-specific AUC(0-tlast) estimates, contrasts, confidence intervals, or p-values are available, preventing assessment of direction, magnitude, or precision. The listed geometric mean and geometric coefficient of variation identify the intended summary but do not supply the values needed to interpret it.

The study was non-randomized and open-label. The registry record does not report baseline characteristics or an adjusted comparison, so the extent to which groups differed on other characteristics is not established. A difference between groups, if reported elsewhere, would not automatically be attributable to renal-function category alone.

The record lists an enrollment of 24 but does not state how many participants contributed evaluable data to each pharmacokinetic outcome. It does not report missing-data rules, handling of incomplete concentration-time profiles, analysis populations, or exclusions. It also does not report the statistical analysis plan, sample-size justification, multiplicity strategy, or interim analyses. The arm descriptions are truncated during the account of Cycle 2 timing, limiting detail on that aspect of the regimen.

Safety reporting is also incomplete for comparative interpretation. Serious and other adverse-event counts are listed, but a statistical comparison and details of event collection are not reported. The denominator basis of the listed serious-event percentages is not stated, and deaths are not reported in the registry record. These limitations constrain what can be concluded from the recorded results, independently of the study’s stated aims.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Pharmacokinetics and Safety of Regorafenib (BAY73-4506) in Cancer Subjects With Severe Renal Impairment — NCT01853046.
• Registry record last updated 2017-02-20; status last verified 2016-12.
• Results first posted 2017-02-20.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

18. Record Summary

NCT01853046 is a completed Phase I, multicenter, non-randomized, open-label, parallel-group study sponsored by Bayer. The registry lists a start in 2013-06, primary completion in 2015-07, and enrollment of 24. It compares cancer subjects with severe renal impairment with a group with normal or mildly impaired renal function.

Participants received regorafenib 160 mg once daily as a single dose in Stage 1, followed by an intermittent multiple-dosing schedule in Stage 2. The primary endpoint was AUC(0-tlast) for regorafenib and active metabolites M-2 and M-5, summarized as a geometric mean with geometric coefficient of variation. Primary endpoint values and comparison estimates are not reported in the registry record.

The registry lists serious and other adverse-event counts by group and several serious-event terms. It does not report a statistical safety comparison, the denominator basis for the term-specific percentages, deaths, a sample-size justification, or detailed analysis methods.