A Study of BBI608 in Combination With Pemetrexed and Cisplatin in Adult Patients With Malignant Pleural Mesothelioma: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study of BBI608 in Combination With Pemetrexed and Cisplatin in Adult Patients With Malignant Pleural Mesothelioma (NCT02347917), a na phase 1, phase 2 study. The primary outcome is Phase 2 Part: Progression-free Survival (PFS).

2. Clinical Question

3. Trial Design

This was an open-label, multicenter Phase 1/II clinical study of BBI608 combined with pemetrexed and cisplatin. Its stated focus was first-line treatment for malignant pleural mesothelioma. The record lists the study as completed, with enrollment of 28. The recorded start was 2015-02, and primary completion was 2018-05-31.

The study model is listed as single group, allocation as not applicable, and masking as none. There is no separate comparator group described in the record. The phases should therefore be understood as parts of a nonrandomized study, not as two randomized arms. The Phase 1 safety group included participants with malignant pleural mesothelioma or non-small cell lung cancer, while the Phase 2 group was described as participants with malignant pleural mesothelioma. Differences between those groups can reflect their distinct phase and population definitions; they do not create a controlled comparison.

The primary endpoint was specified for the Phase 2 part. Efficacy was analyzed in a modified intention-to-treat population, with separate populations listed for Phase 1 (n=4), Phase 2 (n=24), and Phase 2 including one participant with malignant pleural mesothelioma from Phase 1 (n=25). These are analysis-population descriptions, not a breakdown that accounts for all enrollment. The registry record does not explain why the populations differ from the total enrollment.

The record lists secondary outcomes including best overall response, response rate and disease control rate, overall survival, and respiratory function measures. However, it reports 0 analyses, and the numerical efficacy findings are not reported in the registry record. Detailed information about the protocol, treatment schedule, sample-size justification, and any interim analyses is not reported in the registry record.

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: This clinical study consisted of two parts: Phase 1 and Phase 2. The study proceeded to Phase 2 part after Phase 1 part demonstrated the tolerability of BBI608 combined with Pem plus CDDP based on complete assessment of DLT. Participants were NOT enrolled in Phase 1 and Phase 2 in duplicate.

Overall Study

Analysis population for the primary outcome, as defined in the registry: Safety analysis populations (Phase 1 part)

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: Participants were NOT enrolled in Phase 1 and Phase 2 in duplicate.

6. Primary Endpoint

The registry lists the primary outcome as Phase 2 Part: Progression-free Survival (PFS), measured over From BBI608 administration to documented PD or death, whichever is earlier, about 17 months.

Progression-free survival (PFS) measures the time from a defined starting point until disease progression or death, whichever occurs first. In this study the starting point was BBI608 administration, and the primary endpoint was the median PFS for the Phase 2 part. Progression was to be documented according to mRECIST or RECIST 1.1; for Phase 2, the record specifies use of the imaging assessment committee’s imaging assessment results. The stated timeframe was about 17 months.

In general, a time-to-event endpoint uses both the event and the time until it occurs. Participants who have not had the event by the end of observation may contribute information up to their last relevant assessment, rather than being treated as if an event occurred at that time. The registry record does not describe the censoring rules or details of follow-up for this study.

A median is a summary of the event-time distribution: it marks the point at which half the observed population’s event-time distribution lies on either side, subject to the way censored observations are handled. In general, PFS can summarize the duration until progression or death without treating the two events as separate endpoints. It does not, by itself, identify which event occurred first for each participant or describe symptoms, quality of life, or overall survival.

The registry record gives the endpoint definition and says that dispersion was to be expressed with a 95% confidence interval, but it does not report the median estimate or interval. Consequently, the record does not allow readers to judge the numerical PFS result or its precision.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a median time-to-event endpoint represent?

The primary endpoint is median progression-free survival, a time-to-event summary. The clock begins at BBI608 administration. The event is the first of documented progression or death. In general, time-to-event methods are used when participants may have different lengths of observation and when some do not experience the event during their observed follow-up. A participant without a documented event can still contribute information until the point at which observation ends, under the analysis’s censoring rules. The registry record does not report those rules for this study.

A median describes the center of the estimated event-time distribution, rather than an average time or a guaranteed duration for any participant. Its interpretation depends on the event definition, the population analyzed, follow-up, and treatment of censored observations. The record identifies the modified intention-to-treat efficacy population and gives separate Phase 1 and Phase 2 population sizes, but it does not report a median PFS estimate.

How should the confidence interval be understood?

The registry record specifies a 95% confidence interval as the dispersion measure for the primary outcome. In general, a confidence interval conveys the uncertainty of an estimate under the statistical method used. It is not a prediction interval for individual participants and does not mean that a particular proportion of participants’ outcomes lie within its bounds. The interval’s width is relevant to precision, but its actual width and limits are not reported in the registry record. A confidence level alone does not tell readers whether the estimate is precise.

What does the study structure permit?

The study is described as single group, with allocation not applicable and no masking. In general, a randomized controlled comparison can help separate treatment effects from differences between groups, because allocation is designed to balance both known and unknown prognostic factors. This study description contains no randomized comparator. The Phase 1 and Phase 2 parts have different roles, and their populations are not identical: the Phase 1 safety group includes malignant pleural mesothelioma or non-small cell lung cancer, whereas Phase 2 is described for malignant pleural mesothelioma. Therefore, phase-to-phase contrasts cannot be read as controlled estimates of the effect of adding BBI608.

Open-label status means the study was not masked as described in the registry record. In general, awareness of treatment assignment can influence assessments or reporting, especially for outcomes with judgment involved. The record states that Phase 2 imaging was assessed by an imaging assessment committee, but it does not report further details about the committee’s procedures or whether assessments were blinded.

Why does censoring matter for PFS?

In general, censoring occurs when the exact event time is not observed during a participant’s available follow-up. Time-to-event methods can use the information available up to that point without assigning an unobserved event time. The validity of the resulting estimate depends on appropriate analysis assumptions and implementation. For this study, the registry record does not state the censoring convention, handling of missing assessments, or details of follow-up. Those omissions limit an independent assessment of how the endpoint was analyzed.

How should the safety counts be read?

The registry record lists the number at risk and the number affected by serious and other adverse events for each safety group. These are descriptive participant counts. In general, a count of participants affected is different from a count of event episodes: one participant may have more than one event, and a group count alone does not reveal event timing, duration, severity beyond the stated category, or attribution. The record’s listed serious-event terms each have a frequency of 4.2%, but it does not give further event-level details in the registry record. No causal conclusion follows simply from an event occurring during a study.

The safety groups include a Phase 1 group, a Phase 2 group, and a Phase 2 group that includes one Phase 1 participant with malignant pleural mesothelioma. Because the last group incorporates a participant from another group, these are not independent groups to be pooled. The record does not explain the rationale for presenting the overlapping group or provide a controlled safety comparison.

What statistical plan is available?

The registry record reports 0 analyses. It does not report a statistical analysis plan, a sample-size justification, interim analyses, or the numerical results for the primary endpoint. General statistical practice may use prespecified methods to define populations, handle missing observations, and estimate time-to-event outcomes, but the specific methods used in this trial are not reported in the registry record. No method should be attributed to the study beyond the endpoint and analysis-population details that are stated.

10. Multiplicity, Missing Data and Analysis Populations

The registry record lists a primary Phase 2 endpoint and several secondary outcomes: best overall response; response rate and disease control rate; overall survival; and respiratory function tests for vital capacity, forced vital capacity, and forced expiratory volume in the first second. It also lists 10 outcome measures, but reports 0 analyses. Numerical results for the primary and secondary outcomes are not reported in the registry record.

When a study evaluates multiple outcomes or conducts multiple statistical tests, the chance of at least one apparently notable result can increase. In general, a prespecified approach to multiplicity can help clarify which comparisons are confirmatory and how interpretation should account for multiple testing. The registry record does not report a multiplicity strategy, an ordering of secondary outcomes, or which analyses were planned for each measure. It is not possible to determine whether or how multiplicity was addressed.

The efficacy analysis population is described as modified intention-to-treat, with separate Phase 1 (n=4), Phase 2 (n=24), and Phase 2 including one Phase 1 participant with malignant pleural mesothelioma (n=25) populations. The record does not provide the criteria for inclusion in the modified intention-to-treat population, explain why the listed populations differ from enrollment of 28, or report missing-data counts. The reasons for any exclusions, missing observations, or unavailable assessments are not reported in the registry record.

In general, missing outcome information can affect estimates if the probability of missingness is related to participants’ prognosis or outcomes. Interpretation therefore depends on knowing how much information was missing and what assumptions or methods were used. Those details are not reported in the registry record. Without numerical outcome results, denominators for each endpoint, and a description of missing-data handling, readers cannot assess the impact of missingness or reproduce the analyses.

11. Safety Results

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

Deaths

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: colitis (4.2%), enterocolitis (4.2%), gastric ulcer (4.2%), bronchopneumonia (4.2%), sepsis (4.2%).

The registry record presents safety counts for three groups. In the Phase 1 group, 4 participants were at risk for serious adverse events and 0 were affected; 4 were at risk for other adverse events and 4 were affected, with 2 deaths listed. In the Phase 2 group, 24 were at risk for serious adverse events and 7 were affected; 24 were at risk for other adverse events and 24 were affected, with 19 deaths listed. The combined Phase 2 group, including one participant with malignant pleural mesothelioma from Phase 1, lists 25 at risk for serious adverse events and 7 affected, 25 at risk for other adverse events and 25 affected, and 21 deaths.

The combined group overlaps with the Phase 2 group and should not be added to it. The listed serious-event terms are colitis, enterocolitis, gastric ulcer, bronchopneumonia, sepsis, and platelet count decreased; each is reported at 4.2%. The record does not provide further details about event timing, duration, attribution, or whether a participant experienced multiple terms. These counts describe events recorded during the study and do not, on their own, establish that treatment caused an event. The absence of a comparator also limits comparative safety interpretation.

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

The registry record establishes that a Phase I/II, open-label, single-group study evaluated BBI608 with pemetrexed and cisplatin, and that the Phase 2 primary endpoint was median PFS. It defines PFS as time from BBI608 administration to documented progression or death, whichever occurred first, and specifies the assessment criteria used. The study is listed as completed, with enrollment of 28.

Those design and endpoint details do not supply an outcome result. The median PFS and its 95% confidence interval are not reported in the registry record, and the record lists 0 analyses. Thus, readers cannot use this record to quantify the observed PFS or the uncertainty around it. The record also does not give numerical response, disease control, overall survival, or respiratory function results.

Even if numerical results were available, a single-group study would not provide a randomized estimate of how outcomes compare with another treatment. In general, outcomes in a treated group can reflect the treatment, the participants’ characteristics, disease course, assessment practices, and other factors. Without a concurrent comparator and an appropriate comparative design, those influences cannot be separated reliably. Phase 1 and Phase 2 are not interchangeable treatment arms, because their populations and study roles differ.

The serious adverse event counts provide descriptive safety information, but do not by themselves establish causation or comparative risk. They also include an overlapping Phase 2 group that incorporates one Phase 1 participant with malignant pleural mesothelioma. The record lacks details about event attribution and missing safety information.

Accordingly, the registry record supports a description of the study question, design, endpoint definition, analysis populations, and selected safety counts. It does not support a quantitative conclusion about the magnitude or precision of PFS, a treatment comparison, or a causal interpretation of adverse events. Such conclusions would require results and methodological details not reported in the registry record.

13. Why This Trial Matters Statistically

This study illustrates why a clearly stated endpoint is not the same as a reported endpoint result. The registry record defines Phase 2 PFS, identifies the event and time origin, names the assessment criteria, and specifies a 95% confidence interval as the dispersion measure. Yet the numerical median and interval are not reported, and 0 analyses are listed. Statistical interpretation depends on estimates as well as definitions: without the estimate and its uncertainty, the primary outcome cannot be evaluated quantitatively.

The record also illustrates the importance of distinguishing study phases from comparison groups. The Phase 1 and Phase 2 parts do not represent randomized alternatives. Their population descriptions differ, and one listed safety group overlaps with another. Treating these groups as if they were independent arms could create a misleading comparison. Study structure determines which inferences are supported, not just which outcomes were measured.

Finally, the record shows why analysis populations, missing-data handling, and multiplicity plans matter. The efficacy populations are described, but the relationship between those populations and enrollment is not explained. The record lists multiple secondary outcomes but does not report analyses or a multiplicity strategy. In general, these details help readers assess how estimates were generated, what data contributed, and how confidently findings can be interpreted. Their absence is consequential even when the endpoint definitions and safety counts are available.

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 important limitation for interpreting efficacy is that the registry record does not report a numerical primary endpoint result. It gives no median PFS estimate or 95% confidence interval and lists 0 analyses. Numerical findings for the listed secondary outcomes are also not reported. The endpoint timeframe is described as about 17 months, but the record does not provide an observed follow-up summary or clarify how that timeframe relates to individual follow-up.

The single-group design has no randomized control group in the registry description, so it does not support a controlled treatment-effect estimate. The Phase 1 and Phase 2 populations differ, and the Phase 1 group includes participants with malignant pleural mesothelioma or non-small cell lung cancer. The record does not establish that comparisons across phases would be valid.

The relationship between enrollment of 28 and the efficacy populations is not explained. The record does not report eligibility rules for the modified intention-to-treat population, endpoint-specific denominators, missing-data counts, censoring methods, or missing-data handling. It also does not report the statistical analysis plan, multiplicity procedures, sample-size justification, or interim analyses.

Safety information is limited to group counts and selected serious-event terms. The record does not provide event-level timing or attribution, and one safety group overlaps with another. These limitations constrain both efficacy and safety interpretation. Additional protocol and results information is not reported in the registry record.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: A Study of BBI608 in Combination With Pemetrexed and Cisplatin in Adult Patients With Malignant Pleural Mesothelioma — NCT02347917.
• Registry record last updated 2022-04-12; status last verified 2022-04.
• Results first posted 2021-10-01.
• 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

The registry record describes a completed, open-label, multicenter Phase I/II single-group study of BBI608 with pemetrexed and cisplatin for first-line treatment of malignant pleural mesothelioma. Enrollment was 28; the recorded start was 2015-02 and primary completion was 2018-05-31. Allocation is listed as not applicable and masking as none.

The Phase 2 primary endpoint was median PFS, measured from BBI608 administration to documented progression or death, whichever occurred first. The record specifies a 95% confidence interval and describes imaging assessment criteria. Efficacy populations are listed as Phase 1 (n=4), Phase 2 (n=24), and Phase 2 including one Phase 1 participant with malignant pleural mesothelioma (n=25).

The registry record does not report the primary endpoint estimate, its confidence interval, or numerical secondary outcome analyses. It lists safety counts, including serious adverse events and deaths, but provides no controlled safety comparison. Details of the statistical plan, missing-data handling, and sample-size justification are not reported in the registry record.