Safety and Efficacy of Listeria in Combination With Chemotherapy as Front-line Treatment for Malignant Pleural Mesothelioma: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety and Efficacy of Listeria in Combination With Chemotherapy as Front-line Treatment for Malignant Pleural Mesothelioma (NCT01675765), a non-randomized phase 1 study. The primary outcome is Number of Subjects Reporting Adverse Events.

2. Clinical Question

3. Trial Design

The registry describes a completed Phase 1 study, while the official title calls it a Phase 1B study. It lists adults with malignant pleural mesothelioma and an enrollment of 60. The start date is 2014-09-03, the primary completion date is 2018-09-05, and the status is completed. The sponsor is Aduro Biotech, Inc.

The study is classified as nonrandomized, unmasked, and single-group. At the same time, the record lists two intervention regimens: CRS-207 followed by pemetrexed and cisplatin, and cyclophosphamide with CRS-207 followed by the same chemotherapy. Because allocation is nonrandomized, differences between these regimen groups cannot be read as if participants had been assigned at random. The registry record does not report how participants entered each regimen or whether other factors influenced that assignment.

In the regimen without cyclophosphamide, CRS-207 is listed for Weeks 1 and 3. Pemetrexed and cisplatin are listed for Weeks 5, 8, 11, 14, 17 and 20, with up to 6 cycles every 21 days. CRS-207 is listed again for Weeks 23 and 26, followed by maintenance vaccinations every 8 weeks starting at Week 34 until disease progression. In the other regimen, cyclophosphamide is listed with CRS-207 during the initial doses and before later CRS-207 doses. The description of that regimen’s maintenance schedule is incomplete in the registry information, so its full schedule is not reported in the registry record.

The stated purpose is to evaluate safety and induction of an immune response, while the brief summary also describes evaluating objective tumor response. No masking was used. The record does not report further details about the allocation process, a control group, or a prespecified statistical plan.

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.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Safety Analysis Set (all participants who received \>= 1 dose of study treatment)

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 Number of Subjects Reporting Adverse Events, measured over From first study dose until 28 days after the final dose (an average of 44 weeks).

The primary endpoint is the number of participants reporting adverse events. It is a count of participants, rather than a measure of the number of separate event episodes or the severity of every event. The assessment period runs from the first study dose until 28 days after the final dose, described in the registry as an average of 44 weeks. The safety analysis set includes all participants who received at least one dose of study treatment.

Safety outcomes are relevant in a Phase 1 study because they describe the harms reported during exposure to the study regimens. Counting participants with events gives a direct description of how many people in the safety population were reported to have an event, while serious adverse events provide a more specific view of serious events. These counts do not, by themselves, determine whether an event was caused by treatment. They also do not describe event duration, severity beyond the serious-event classification, or whether an individual participant experienced multiple events.

The record contains serious-event and other-event counts by regimen, but does not provide a complete breakdown of every adverse event by type, severity, timing, or attribution in the registry record for this analysis. Nor does it report a formal statistical comparison for the primary endpoint. The results should therefore be read as descriptive safety information, not as a test establishing a difference between regimens.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is a participant count. For this type of outcome, the basic descriptive information is the number of participants with the event and the number included in the relevant safety population. The registry reports those counts for serious and other adverse events in the two listed regimen groups. A count is interpretable as a description of the observed safety population, but it is not automatically an estimate of treatment effect.

What does a confidence interval express?

General statistical explanation: a confidence interval describes the uncertainty around an estimated quantity under a specified statistical model and method. It helps readers distinguish an estimate that is relatively precise from one that is compatible with a wider range of values. The registry entries available for this analysis do not report confidence intervals for the posted adverse-event counts or a treatment-group contrast. Without an interval or other uncertainty measure, the raw counts alone do not show how precisely a difference between regimens has been estimated.

Why is the allocation method important?

General statistical explanation: random allocation is designed to make treatment groups comparable, on average, with respect to both measured and unmeasured characteristics. In a nonrandomized study, group membership may be associated with participant characteristics or other factors. This means that a raw difference in outcomes can reflect those factors as well as any treatment-related difference. Here, the registry identifies allocation as nonrandomized, and the registry entries available for this analysis do not describe how participants were assigned to the two regimens. The group results should consequently be treated as descriptive rather than as a causal comparison.

What does a safety count capture?

General statistical explanation: a participant-level count records whether a participant experienced an event within the stated assessment period. It does not necessarily capture how many episodes occurred, how long they lasted, or whether several event terms occurred in the same participant. A serious-event count also does not alone establish that an event was caused by a study treatment. The registry’s primary endpoint is described as a count of participants with incidences of adverse events, while the posted group information separates serious and other events. Details about event attribution and the full event-level analysis are not reported in the registry record.

How should the listed event percentages be read?

The record lists percentages for several serious adverse event terms, but the denominator and calculation basis are not specified in the available information. General statistical explanation: a percentage is only fully interpretable when its numerator, denominator, event definition, and analysis population are clear. Event categories can overlap because a participant may experience more than one type of event. The listed percentages should therefore be read as registry-reported figures for those terms, not as parts of a total that can be added together.

What do planning calculations mean?

General statistical explanation: sample-size calculations estimate how many participants may be needed under particular assumptions to detect a specified effect with a chosen statistical procedure. The registry’s planning assumptions describe a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The calculation is described as using a stated fraction of the observed effect. For non-time-to-event outcomes, the intended output is participants per arm; time-to-event calculations are described as using a total event count. These are planning illustrations, not observed power and not proof that the study had adequate power for its questions. No numerical illustration is included in the registry record for this analysis, and the trial’s own sample-size justification is not reported in the registry record.

What can be concluded from the analysis record?

The registry lists zero analyses. That means the registry entries available for this analysis do not include a reported inferential analysis for the outcomes described. It does not establish why an analysis is absent or whether analyses were conducted outside the registry. Statistical procedures for adjustment, handling of missing outcomes, subgroup analysis, and multiplicity are not reported in the registry record. Conclusions should stay within the descriptive information actually posted: group-specific event counts and the listed serious-event terms and percentages.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("Immunotherapy Plus Chemotherapy", "Immunotherapy With Cyclophosphamide Plus Chemother")
n      <- c(38, 22)
events <- c(38, 22)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Immunotherapy Plus Chemotherapy  38  38  100.0  90.7  100.0  90.8  100.0  91.0  99.9
ARM  Immunotherapy With Cyclophosphamide Plus Chemother  22  22  100.0  84.6  100.0  85.1  100.0  85.2  99.9

11. Multiplicity, Missing Data and Analysis Populations

The registry lists multiple outcomes: adverse events as the primary outcome, and objective tumor response, time to progression, and serum mesothelin as secondary outcomes. Testing or estimating several outcomes raises questions about how the analysis plan handles multiple comparisons and which results are intended to be confirmatory. The record does not report a multiplicity strategy, such as an adjustment procedure or a hierarchy for interpreting outcomes. The absence of that information means the status of any potential secondary-outcome findings as exploratory or confirmatory is not reported in the registry record.

Missing-data methods are also not reported in the registry record. The primary safety population is defined as all participants who received at least one dose of study treatment, but the registry entries do not state how participants with incomplete follow-up were handled, whether follow-up differed among participants, or how missing event information was treated. The endpoint’s assessment period extends from first dose until 28 days after the final dose, described as an average of 44 weeks; the record does not provide participant-level follow-up durations or a distribution of exposure time.

The safety counts are presented by the two listed regimens, but a complete analysis population flow, reasons for exclusion, and analysis populations for the secondary outcomes are not reported in the registry record. The registry also lists zero analyses in the registry record for this analysis. This limits the ability to assess the planned statistical treatment of the outcomes or the consequences of incomplete data. These omissions do not establish that data were missing or that a particular method was used; they mean the relevant details are not reported in the registry record.

12. 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: pneumonia (9.1%), dyspnoea (7.9%), constipation (5.3%), nausea (5.3%), vomiting (5.3%).

The registry reports serious adverse events in 15 of 38 participants receiving immunotherapy plus chemotherapy and in 11 of 22 receiving immunotherapy with cyclophosphamide plus chemotherapy. It reports other adverse events in 38 of 38 and 22 of 22 participants, respectively. These are participant counts within the listed safety groups, not event totals. The registry also lists 3 deaths in the first group and 0 in the cyclophosphamide group.

These figures do not show whether events were judged related to treatment, and the death counts do not state cause or timing. The group allocation was nonrandomized, so raw differences should not be interpreted as evidence that one regimen caused more or fewer events. The record does not report uncertainty intervals for the group counts or a formal comparison. The serious-event terms and percentages are registry-listed descriptions; the available information does not specify their denominators or whether event categories overlap. Read the figures as descriptive safety reporting, not as a causal assessment.

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

The result that can be described from the registry is the number of participants reported with serious and other adverse events in each listed safety group, together with a set of serious-event terms and percentages. The primary endpoint is safety-focused. These posted counts describe what was recorded in the treated participants during the stated assessment period, which runs from first study dose until 28 days after the final dose and is described as an average of 44 weeks.

The figures do not establish that CRS-207, cyclophosphamide, pemetrexed, or cisplatin caused a particular event. They do not determine whether an individual event was preventable, treatment-related, or clinically consequential beyond its reported classification. They also do not establish that adding cyclophosphamide changes safety: the regimen groups were nonrandomized, and the registry does not report an adjusted comparison or uncertainty interval.

The registry’s stated aims include immune response and objective tumor response, and its secondary outcomes include time to progression and serum mesothelin as a correlate of therapeutic response. Numerical findings for those outcomes are not reported in the registry record in the registry record for this analysis. The safety figures therefore cannot answer whether tumor response occurred or how long participants remained free of progression.

The record describes a completed study, but completion status is not itself evidence about the results or their precision. The listed enrollment of 60 is not a substitute for an analysis of how many participants contributed to each outcome. The safety group counts are reported separately, and the record does not provide further population-flow details. No conclusions about efficacy, comparative benefit, or the generalizability of results follow from these safety counts alone.

14. Why This Trial Matters Statistically

This trial raises statistical questions that are common in early-phase studies combining immunotherapy and chemotherapy. The registry’s primary endpoint counts participants reporting adverse events, making the outcome directly relevant to describing safety during treatment. At the same time, the treatment sequence is complex: CRS-207 is administered before chemotherapy, and one regimen includes cyclophosphamide. Interpreting events within such regimens requires clarity about timing, attribution, exposure, and the population included in the analysis.

The study also illustrates the difference between describing two groups and making a comparative claim. Although two regimens are listed, allocation is nonrandomized and the record labels the study single-group. A numerical contrast between groups would not, by itself, separate regimen effects from differences in who received each regimen. That distinction matters when readers encounter group-specific safety counts or any planning illustration based on an observed effect.

Another statistical issue is the relationship between the primary safety question and the listed secondary outcomes. Tumor response, time to progression, and serum mesothelin address different aspects of the study’s aims and require distinct outcome definitions and analyses. The numerical results and the analysis plan for those outcomes are not reported in the registry record in the registry record for this analysis. Readers therefore need to distinguish stated aims from posted findings.

The record also makes clear why analysis details matter. The safety population is defined, but missing-data methods, multiplicity handling, and inferential analyses are not reported. Those details affect how precisely and confidently results can be interpreted. The trial is statistically informative as an example of how study design, outcome definition, and reporting completeness constrain what can be concluded from observed event counts.

15. 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 design is nonrandomized, and the registry identifies the study as single-group while listing two treatment regimens. The available information does not describe how participants entered each regimen or whether assignment reflected clinical or other considerations. Consequently, the groups are not a like-for-like randomized comparison, and differences in their observed event counts cannot be attributed to the regimen difference alone.

The posted safety information does not include confidence intervals, adjusted estimates, or a reported inferential analysis. The registry lists zero analyses in the registry record for this analysis. Detailed outcome results for objective tumor response, time to progression, and serum mesothelin are not reported in the registry record. The registry record also does not report the sample-size justification, missing-data approach, multiplicity plan, or methods for handling incomplete follow-up.

Although the safety analysis set is defined as participants who received at least one dose, further details about population flow, exposure, and follow-up are not reported in the registry record. The average assessment duration is stated, but individual follow-up durations are not available in the registry record for this analysis. The denominator and calculation basis for the listed serious-event percentages are likewise not reported in the registry information.

The description of the cyclophosphamide regimen’s maintenance schedule is incomplete in the available record. The event counts do not specify attribution to study treatment, and the death counts do not state cause or timing. These limitations restrict interpretation to a descriptive account of the recorded safety counts rather than a causal comparison or a full assessment of treatment efficacy.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Safety and Efficacy of Listeria in Combination With Chemotherapy as Front-line Treatment for Malignant Pleural Mesothelioma — NCT01675765.
• Registry record last updated 2020-09-30; status last verified 2020-09.
• Results first posted 2020-09-30.
• 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.

19. Record Summary

The registry record describes a completed Phase 1 study, identified as Phase 1B in the official title, of CRS-207 with pemetrexed and cisplatin, with or without cyclophosphamide, in adults with malignant pleural mesothelioma. The study is listed as nonrandomized, unmasked, and single-group, with an enrollment of 60. The primary outcome counts participants reporting adverse events in a safety population of participants who received at least one dose.

The posted safety counts include serious and other adverse events for both listed regimens, as well as deaths and selected serious-event terms. The registry also lists objective tumor response, time to progression, and serum mesothelin as secondary outcomes. Numerical results for those outcomes, a formal statistical analysis, and details of missing-data and multiplicity methods are not reported in the registry record in the registry record for this analysis.