Pharmacokinetics Study of Oral Ixazomib (MLN9708) in Relapsed/Refractory Multiple Myeloma and Advanced Solid Tumors Participants With Normal Renal Function or Severe Renal Impairment: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Pharmacokinetics Study of Oral Ixazomib (MLN9708) in Relapsed/Refractory Multiple Myeloma and Advanced Solid Tumors Participants With Normal Renal Function or Severe Renal Impairment (NCT01830816), a non-randomized phase 1 study. The primary outcome is Unbound Cmax: Unbound Maximum Observed Plasma Concentration for Ixazomib.

2. Clinical Question

3. Trial Design

This was a Phase 1 pharmacokinetics study of oral ixazomib, also identified in the study title as MLN9708. It was non-randomized, unmasked, and classified as a single-group model, while the registry separately describes groups by renal function: normal renal function, severe renal impairment, and end-stage renal disease. These categories do not constitute randomized comparisons. Differences between them could reflect differences in the participants or their disease circumstances as well as renal status; the record does not report an adjusted comparison that would separate such factors.

The study concerned participants with relapsed/refractory multiple myeloma and advanced solid tumors. Its stated purpose was to characterize single-dose pharmacokinetic parameters in people with normal renal function or severe renal impairment, including end-stage renal disease. The overall enrollment was 41. The arm descriptions state that participants received one oral 3.0 mg dose during the 15 day Part A period. Participants could continue into Part B, where the description refers to ixazomib doses of 4, 3, or 2.3 mg per protocol. The full Part B schedule is not reported in the registry record, so it cannot be described further.

The study started on 2013-09-16, reached primary completion on 2015-03-03, and is recorded as completed. The registry lists six outcome measures, including adverse events, overall response, and duration of response among the secondary outcomes. It does not report the primary pharmacokinetic result in the information available for this analysis. The listed secondary outcome names alone do not establish what those outcomes showed.

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: Participants with a diagnosis of relapsed or refractory multiple myeloma (RRMM) or advanced solid tumors who had normal renal function or severe renal impairment including end-stage renal disease requiring hemodialysis (ESRD) were enrolled to receive ixazomib orally in the study.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Pharmacokinetic (PK) evaluable population was defined as participants who received protocol-specified single dose in Part A; did not receive any excluded concomitant medications through the completion of PK sampling; and had sufficient concentration-time data to permit reliable estimation of PK parameters by non-compartmental analysis methods.

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.

Population: Safety population is defined as participants who received at least 1 dose of study drug.

6. Primary Endpoint

The registry lists the primary outcome as Unbound Cmax: Unbound Maximum Observed Plasma Concentration for Ixazomib, measured over Part A, Day 1: Predose and at multiple timepoints (up to 336 hours) post-dose.

The primary endpoint is unbound Cmax, described as the unbound maximum observed plasma concentration of ixazomib. Cmax identifies the highest measured concentration in the sampling period; “unbound” specifies the fraction of the drug measured as not bound to plasma components. This endpoint is used in pharmacokinetic studies to describe peak exposure after dosing. It is a concentration measure, not a direct measure of clinical benefit or harm.

Sampling was scheduled from predose through multiple time points up to 336 hours after the dose on Part A, Day 1. The registry specifies a geometric mean as the summary measure and standard deviation as the dispersion measure. In general, a geometric mean is useful for summarizing positive measurements that vary multiplicatively or are right-skewed. A standard deviation describes variability around a summary, although its interpretation alongside a geometric mean depends on the scale and method used for the analysis.

The pharmacokinetic evaluable population was defined by receiving the protocol-specified Part A single dose, having no excluded concomitant medications through the end of pharmacokinetic sampling, and having sufficient concentration-time data for reliable estimation of pharmacokinetic parameters. The registry record does not report the endpoint values, group-specific estimates, confidence intervals, or a statistical comparison. As a result, the endpoint’s definition and planned summary can be described, but the magnitude and precision of the observed unbound Cmax cannot be interpreted from the record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry identifies unbound Cmax as the primary endpoint and geometric mean with standard deviation as its summary. It does not provide an endpoint estimate or an inferential analysis. The statistical interpretation is consequently limited to explaining what the measure and stated summaries mean, rather than evaluating an observed treatment effect.

What does unbound Cmax measure?

Concentration-time data record drug concentrations at planned times after dosing. Cmax is the highest observed concentration within the sampling window. It is “observed” because it is based on sampled measurements rather than necessarily being a directly measured concentration at the exact biological peak. The unbound designation refers to the portion of ixazomib not bound to plasma components. The record gives the sampling timeframe as predose and multiple time points up to 336 hours after the Part A, Day 1 dose.

In general, peak concentration is one way to characterize drug exposure. It does not summarize the entire concentration-time profile, and it does not by itself establish how long a concentration persists. Nor is it a clinical outcome such as response or duration of response. The registry lists those as separate secondary outcomes for participants with relapsed/refractory multiple myeloma, but does not report their results in the information used.

Why use a geometric mean?

In general, a geometric mean summarizes positive values on a multiplicative scale. It is often used when measurements are skewed or when relative changes are more natural to consider than absolute differences. It is calculated by averaging on a logarithmic scale and converting back to the original scale. No numerical endpoint data are reported, so no geometric mean can be interpreted or reconstructed.

The registry names standard deviation as the dispersion measure. In general, standard deviation describes variability around a summary, but the scale matters: a standard deviation expressed on the original concentration scale is not interpreted in exactly the same way as variability on a logarithmic scale. The registry record does not specify the transformation or the exact calculation used for the endpoint summary. It also does not report a confidence interval. A confidence interval, in general, represents a range of values compatible with the data and the statistical method; it helps communicate precision rather than proving that a particular value is true.

Who was included in the pharmacokinetic analysis?

The record defines a pharmacokinetically evaluable population. Participants had to receive the protocol-specified single dose in Part A, have no excluded concomitant medications through completion of pharmacokinetic sampling, and have sufficient concentration-time data for reliable estimation of pharmacokinetic parameters. This definition means that overall enrollment and the endpoint analysis population are not interchangeable. The number meeting the evaluability criteria in each renal-function category is not reported in the registry record.

In general, an analysis restricted to evaluable participants can be affected if exclusions are related to participant characteristics, dosing, or observed concentrations. Clear reporting of the numbers assessed, excluded, and analyzed, together with reasons for exclusion, helps readers assess that possibility. The registry information does not provide these details for the primary endpoint. It also does not state how concentrations below a measurement limit, incomplete sampling, or other missing observations were treated.

What can the study design support?

This was a non-randomized study with renal-function categories and no like-for-like control comparison. In general, randomization can help balance measured and unmeasured characteristics between treatment groups. Here, participants were not randomly assigned to renal status, and renal categories may differ in other ways. A simple contrast between category summaries, if one were reported, would be descriptive and could not by itself establish that renal function caused the difference.

The registry does not describe a statistical model, covariate adjustment, hypothesis test, significance threshold, or confidence-interval method for the primary endpoint. Those methods are not reported in the registry record. No sample-size justification or interim-analysis plan is reported either. It would be inappropriate to infer these design choices from the Phase 1 label, the enrollment, or the study’s pharmacokinetic purpose.

In general, over-dispersion occurs when observed variability exceeds what a chosen statistical model assumes. Accounting for it can matter when a model’s standard errors depend on an overly restrictive variability assumption. The registry record does not state that over-dispersion was assessed or that a model requiring such an adjustment was used; this is a general statistical consideration, not a reported feature of this analysis.

Overall, the record provides an endpoint definition and an evaluability rule, but no numerical primary result or inferential details. The appropriate statistical reading is therefore descriptive: the study was designed to characterize a pharmacokinetic measure across renal-function categories, while the posted record does not contain enough primary-endpoint information to assess the estimate, its variability, or a between-category difference.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists six outcome measures, including the primary pharmacokinetic endpoint and secondary outcomes concerning adverse events, overall response, and duration of response in participants with relapsed/refractory multiple myeloma. It does not report how multiplicity was handled. In general, testing multiple outcomes can increase the chance of at least one apparently notable finding when each is considered separately. A statistical plan may address this through a hierarchy, adjustment, or a clearly designated descriptive role for secondary outcomes, but the plan is not reported in the registry record.

The record does not give a formal hypothesis-testing plan for unbound Cmax, including a stated null hypothesis, significance threshold, confidence-interval method, or adjustment for comparisons across renal-function categories. It also does not report a sample-size justification. These details cannot be inferred from the phase, design, enrollment, or endpoint name.

The primary endpoint’s evaluable-population definition requires specified dosing, no excluded concomitant medications through sampling completion, and sufficient concentration-time data. However, the number excluded, reasons for exclusion, and handling of incomplete or missing concentration measurements are not reported in the registry record. It is therefore not possible to assess whether missingness could have influenced the endpoint summary or how the analysis population differed from those enrolled.

In general, missing-data methods should match the reason and structure of missingness; excluding incomplete records is not automatically neutral. The record does not state whether missing values were imputed, whether all available measurements were used, or whether sensitivity analyses were performed. No interim analyses or related statistical procedures are reported. These absences limit assessment of the analysis process, but do not establish that any particular method was or was not used outside what the registry record reports.

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: gastrointestinal haemorrhage (14.3%), dyspnoea (14.3%), plasma cell myeloma (14.3%), pneumonia (7.1%), sepsis (7.1%).

The registry lists serious adverse event counts for each renal-function group: 3 affected participants among 20 at risk in the normal renal function group, 6 among 14 at risk in the severe renal impairment group, and 3 among 7 at risk in the end-stage renal disease group. It also lists other adverse event counts: 19 among 20, 14 among 14, and 5 among 7, respectively. These are descriptive counts in the posted safety information, not evidence that ixazomib caused each event or that groups differ because of renal function.

Selected serious-event terms are listed with registry-reported percentages: gastrointestinal haemorrhage, dyspnoea, and plasma cell myeloma at 14.3% each; pneumonia, sepsis, and pancreatitis acute at 7.1% each. The record does not identify the denominator for these term percentages in the information summarized, so they should not be converted into counts or assigned to a subgroup. Event terms can also reflect underlying cancer and other clinical circumstances; the registry listing alone does not establish attribution.

Deaths are not reported as a numeric result in the registry record. That absence should not be read as evidence that no deaths occurred. The safety counts do not supply the missing primary pharmacokinetic results.

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

This record describes a Phase 1 study intended to characterize single-dose ixazomib pharmacokinetics in cancer participants across recorded renal-function categories. It identifies unbound maximum observed plasma concentration as the primary endpoint and specifies a geometric mean and standard deviation as its summary. The endpoint is a drug-concentration measure intended to describe exposure, rather than a direct measure of tumor response, survival, or clinical benefit.

The record does not report the primary endpoint’s numerical findings. It therefore does not establish the observed unbound Cmax in any category, the amount of variability, or the precision of an estimate. It also does not support a conclusion about whether the categories had similar or different pharmacokinetic results. A missing registry result is not evidence of no difference or of equivalence.

The study was non-randomized and did not use a like-for-like control comparison. Thus, the renal-function groups are not randomized treatment arms. Even if estimates were reported, differences between groups would need to be interpreted in light of the design and any analytical adjustments. The registry does not report an adjusted comparison or statistical model for the primary endpoint.

The posted safety information gives adverse-event counts by group and several serious-event terms with percentages. These are descriptive safety data, not proof of causation, and the record does not report a numeric death result. Secondary outcome names are listed, but their results are not reported in the information. The record consequently supports a description of the research question, design, endpoint definition, and selected safety counts, but not a judgment about pharmacokinetic effect size, clinical outcomes, or comparative safety.

13. Why This Trial Matters Statistically

Pharmacokinetic studies ask how drug concentrations behave over time, and renal-function categories can be relevant when researchers are characterizing exposure in different clinical populations. This study’s stated aim was to characterize single-dose ixazomib pharmacokinetic parameters in cancer participants with normal renal function or severe renal impairment, including end-stage renal disease. Its primary endpoint, unbound Cmax, focuses on peak unbound plasma concentration after dosing.

Statistically, the record illustrates why a clearly named endpoint is only one part of interpreting a study. The summary method and endpoint definition are reported, but the numerical endpoint result, uncertainty measure, and analysis details are not. Without those elements, readers cannot assess the size, variability, or precision of the primary estimate. The distinction between overall enrollment and the pharmacokinetically evaluable population also matters: the endpoint definition imposes data and dosing requirements, while the number meeting them is not reported.

The non-randomized design is another important feature. Renal-function categories are not interchangeable with randomized treatment groups, so descriptive contrasts should not be treated as causal comparisons. Reporting group-specific estimates and their uncertainty, together with the analysis population and statistical methods, would be necessary for a fuller evaluation of the pharmacokinetic evidence. The registry record does not supply these details.

The safety listings add descriptive information, but do not resolve the primary endpoint question or demonstrate causation. Taken together, the record is useful for identifying the study’s purpose, framework, and outcome definitions, while also showing the limits of interpretation when outcome estimates and analysis details are not reported.

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 main limitation for interpreting this trial from the registry record is that no numerical result is reported for the primary endpoint, unbound Cmax. Group-specific estimates, variability values, confidence intervals, and a statistical comparison are also absent. The study’s stated summary method alone cannot show what was observed or how precise the estimate was.

The pharmacokinetic evaluable population is defined, but its size by renal-function category is not reported. Nor are the numbers excluded from that population or the reasons for exclusion. This leaves uncertainty about how the analyzed participants relate to overall enrollment. The record also does not describe how missing or incomplete concentration-time data were handled.

The non-randomized design limits causal interpretation of any hypothetical differences across renal-function categories. The record does not report adjusted analyses that might account for group differences, and it does not provide a statistical model or comparison method. A sample-size justification, formal statistical plan, multiplicity approach, and interim-analysis information are not reported in the registry record.

The arm descriptions do not give the complete Part B dosing schedule, so the extension portion cannot be fully characterized. Secondary outcomes are named, but their results are not reported in the available information. Safety details include selected event counts and terms, but the registry does not provide a numeric death result or identify the denominator for the listed serious-event term percentages in the information summarized. These limitations restrict conclusions to the study’s design, definitions, and posted descriptive safety information.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Pharmacokinetics Study of Oral Ixazomib (MLN9708) in Relapsed/Refractory Multiple Myeloma and Advanced Solid Tumors Participants With Normal Renal Function or Severe Renal Impairment — NCT01830816.
• Registry record last updated 2019-06-10; status last verified 2019-03.
• Results first posted 2019-06-10.
• 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

This completed Phase 1, non-randomized, unmasked study examined oral ixazomib in participants with relapsed/refractory multiple myeloma or advanced solid tumors. Overall enrollment was 41. The registry describes normal renal function, severe renal impairment, and end-stage renal disease groups. In Part A, participants received a single oral 3.0 mg dose during a 15 day period; the description says some could continue into Part B but does not give the complete dosing schedule.

The primary endpoint was unbound maximum observed plasma concentration, summarized as a geometric mean with standard deviation, using a defined pharmacokinetically evaluable population. The registry record does not report the primary endpoint result, its uncertainty, or an inferential comparison. It lists six outcome measures, including adverse events, overall response, and duration of response, but the listed outcome names do not establish their results. Serious and other adverse-event counts are reported by group, alongside selected serious-event terms. The study started on 2013-09-16, reached primary completion on 2015-03-03, and is recorded as completed.