Study of the Safety and Efficacy of Amatuximab in Combination With Pemetrexed and Cisplatin in Subjects With Unresectable Malignant Pleural Mesothelioma (MPM): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study of the Safety and Efficacy of Amatuximab in Combination With Pemetrexed and Cisplatin in Subjects With Unresectable Malignant Pleural Mesothelioma (MPM) (NCT02357147), a randomized phase 2 study. The primary outcome is Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs).

2. Clinical Question

The study was designed to assess the safety and efficacy of adding amatuximab to pemetrexed and cisplatin in this population. The posted primary outcome is specifically the number of participants with AEs and SAEs. It does not, by itself, describe how often events occurred, how long they lasted, or their severity beyond the serious/non-serious distinction. The endpoint description also notes that one participant could be counted among those with SAEs and among those with non-SAEs.

The registry record reports safety counts for both the combination and maintenance phases. The question of interest is therefore descriptive: what participant counts were recorded for each treatment-phase group? The record does not report a formal statistical comparison of these counts, nor does it identify a separate primary efficacy result in the posted outcome data.

3. Trial Design

This was a phase 2, randomized, parallel-group study with placebo control and quadruple masking. It was designed as a multicenter study in participants with unresectable malignant pleural mesothelioma who had not received prior systemic therapy. The registry enrollment is 124. Morphotek is listed as the sponsor.

In the combination phase, one arm received amatuximab with pemetrexed and cisplatin; the other received placebo with pemetrexed and cisplatin. The arm descriptions then identify maintenance treatment with amatuximab or placebo, respectively. The planned amatuximab regimen was 5 milligrams per kilogram weekly. The registry lists the study as terminated.

The brief summary explains that a sponsor business decision led to a protocol amendment. Participants randomized to amatuximab who were still receiving active treatment at the amendment could consent to continue weekly amatuximab until disease progression or intolerable toxicity, at the principal investigator’s discretion. Participants randomized to placebo, and participants who were in follow-up when the amendment occurred, were discontinued from the study. The registry record does not give further details about the decision or its timing.

The reported safety endpoint uses a safety analysis set defined as randomized participants who received at least 1 dose of study drug. The registry reports participant counts separately for the combination and maintenance phases. The phase-specific counts should be read in light of the treatment discontinuation and continuation described in the record; the maintenance figures do not represent a newly randomized comparison.

Details of the randomization sequence, allocation concealment, masking procedures, and planned statistical analysis are not reported in the registry record. The record also does not report a sample-size justification or explain whether the enrollment was changed after termination.

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: A total of 124 participants were enrolled (signed informed consent form), of which, 16 were screen failures, 108 were randomized, and 106 were treated. Deaths that were primary cause of treatment discontinuation are reported in participant flow excluding those that occurred after treatment discontinuation.

Combination Treatment Phase

Reasons for not completing this period:

Maintenance Treatment Phase

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The safety analysis set was defined as all randomized participants who received at least 1 dose of study drug.

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: The safety analysis set was defined as all randomized participants who received at least 1 dose of study drug.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs), measured over Baseline up to 3 years.

The primary endpoint is the number of participants with adverse events (AEs) and serious adverse events (SAEs), with a timeframe from baseline up to 3 years. It is a participant-count endpoint: it records whether participants experienced events, rather than the total number of event episodes or the time until an event.

The endpoint description says AEs include both non-serious and serious events. The same participant can have both, so the categories are not mutually exclusive. A participant count in each category should not be added to produce a unique overall count. The registry does not report a combined total of unique participants with any AE.

As a general statistical principle, safety endpoints are used to characterize harms observed during treatment and follow-up. Reporting serious and non-serious events separately can help distinguish events classified as serious from other events, while still documenting the broader burden of reported AEs. These counts do not establish that treatment caused an event: the registry’s endpoint records participants with events, and the record does not report a causal attribution analysis.

The posted endpoint does not capture the full clinical detail of each event, such as its duration, recurrence, severity grade, or relationship to treatment. Those details are not reported in the registry record as part of this outcome measure.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry reports a binary safety outcome as participant counts: whether participants experienced an SAE or a non-serious AE. A count of participants affected is different from a count of event episodes. One participant may experience more than one event, but the posted outcome reports participants, not the number of episodes. The endpoint description also explicitly allows the same participant to appear in both the serious and non-serious categories.

What does a participant count represent?

For each phase and treatment group, the registry gives the number of participants at risk and the number affected. The at-risk count is the denominator associated with that group’s reported outcome. It is not appropriate to add the affected counts across categories to infer a number of unique participants, because the categories can overlap. The record also reports deaths separately; it does not define these as an additional non-overlapping category or explain their relationship to the AE counts.

The term “at risk” in the registry’s displayed outcome is the count used for the phase-specific safety summary. It should not be read as proof that every participant had identical follow-up time or an identical opportunity to experience an event. The outcome timeframe spans baseline up to 3 years, but the registry does not report participant-level observation time or the timing of individual events.

Why do counts not establish a treatment effect?

Random allocation is intended to support a fair comparison of treatment groups, but a numerical difference in observed counts is not itself an inferential result. Statistical inference considers both the estimated difference and its uncertainty. A confidence interval, as a general statistical concept, describes a range of values compatible with the data and the method used; the registry record does not report confidence intervals for these counts. A p-value, as a general concept, evaluates how compatible data are with a specified null model; the registry record does not report p-values or a specified null model for this endpoint.

For an event-count outcome, uncertainty depends in part on the number of participants and on how frequent the event is. When events are uncommon, estimates can be imprecise, and a small change in the observed count can matter substantially to an estimated rate. Rates also require a defined time basis if follow-up differs. The registry provides participant counts and phase-specific at-risk counts, but does not report event rates per person-time or methods that account for differing observation times.

What changes across treatment phases?

The combination and maintenance results are reported separately. A valid interpretation of the maintenance figures depends on who entered that phase, how follow-up was handled, and how discontinuation affected observation. The study summary states that some participants could continue amatuximab after a protocol amendment, while placebo participants and participants already in follow-up were discontinued. The record does not report an analysis that accounts for these changes. Maintenance counts therefore describe the registry’s phase-specific groups and should not be treated as if a new random assignment occurred at the start of maintenance.

As a general principle, analyses that compare groups after selection into a later treatment phase can be affected by differences in who remains eligible or observed. Randomization at study entry does not automatically remove selection that occurs later. The registry does not report a method for addressing this issue or enough detail to characterize the pattern of follow-up by participant.

What do the planning illustrations mean?

Planning sample-size calculations are distinct from observed results. The calculation approach described for this record uses a two-sided significance level of 0.05, equal allocation, and a normal approximation, with an effect to detect defined as a stated fraction of the observed effect. Such calculations are conditional illustrations: they show what sample size would be associated with specified assumptions, not the probability that the completed trial found a true effect. They are not observed power, and they do not substitute for an analysis of the trial data. The record does not report a sponsor sample-size justification or state that the trial was originally designed around these recalculated assumptions.

More generally, a planned sample size depends on assumptions about the target effect, variability or event frequency, significance level, power, and analysis method. If those assumptions do not match the study’s eventual data or design, the resulting illustration may not describe the trial’s original planning. The registry record does not report the sponsor’s assumptions for these elements.

Which statistical procedures were used?

The registry does not report an inferential procedure for the primary safety endpoint. It does not specify a model, a confidence-interval method, adjustment for covariates, handling of missing outcome data, or a strategy for multiple comparisons. It is therefore not possible to attribute a particular statistical method to the sponsor from the registry record. Any explanation of confidence intervals, p-values, or planning calculations above is general statistical context rather than a description of an analysis documented for this trial.

10. Multiplicity, Missing Data and Analysis Populations

The primary safety outcome includes serious and non-serious AE categories, and results are reported for combination and maintenance phases. The record does not identify a single contrast as the primary statistical comparison or state how multiple categories or comparisons were handled. A multiplicity plan, including any adjustment to significance thresholds or hierarchy of tests, is not reported in the registry record. No inferential analyses are posted for this endpoint, so there are no reported p-values whose interpretation can be assessed for multiplicity.

Missing-data handling is also not reported in the registry record. The outcome description gives the timeframe as baseline up to 3 years, but does not explain how incomplete follow-up, withdrawals, or participants without a recorded event were handled. The record does not provide participant-level follow-up durations or describe imputation, censoring, or sensitivity analyses. Consequently, the degree to which differing observation time or missing information could affect the counts cannot be evaluated from the posted results.

The safety analysis set is defined as all randomized participants who received at least 1 dose of study drug. This is the stated population for the safety outcome; the record does not provide a separate intention-to-treat efficacy analysis population. It also does not report whether every randomized participant received a dose, or explain exclusions from the safety set. The protocol amendment and discontinuation described in the study summary are relevant to interpretation, but the record does not report a statistical approach for handling those changes.

Interim analyses, stopping rules, and a statistical analysis plan are not reported in the registry record. The study is listed as terminated, but the record does not state that termination followed a statistical stopping boundary.

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: nausea (5.8%), amaurosis (4.0%), diarrhoea (3.8%), lower respiratory tract infection (3.8%), urinary tract infection (3.8%).

The serious adverse-event figures are participants affected within each treatment-phase group, alongside the number at risk. In the combination phase, the reported counts are 15 of 52 for amatuximab and 11 of 54 for placebo. In maintenance, the counts are 1 of 25 for amatuximab and 4 of 29 for placebo. The phase-specific at-risk counts differ, and the registry does not report a formal statistical comparison of these figures.

These counts do not describe the number of serious-event episodes: one participant may have more than one SAE. They also do not show event timing, duration, severity grade, or treatment relatedness. The registry lists deaths separately, but does not report whether they were related to an SAE or considered treatment-related.

The listed serious-event terms and percentages are descriptive. Since the record does not state their denominators or calculation method, they should not be interpreted as rates or as evidence of a comparative effect. In general, safety summaries help describe observed events; causal attribution requires evidence and methods beyond a simple count.

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

The posted results establish that the registry recorded participants with serious and non-serious adverse events in the amatuximab and placebo groups, during both combination and maintenance treatment. They also provide phase-specific at-risk counts and a separate listing of deaths. This information describes the safety observations recorded for the trial; it does not establish that a particular treatment caused an event.

The results do not provide a precise estimate of the difference between treatment groups. The registry record reports no confidence intervals, p-values, adjusted comparisons, or event-rate analyses for the primary safety outcome. The counts therefore cannot show how much uncertainty surrounds any apparent difference. They should not be converted into claims of statistical significance or equivalence.

The endpoint concerns the number of participants with AEs and SAEs, not tumor response, disease progression, quality of life, or survival. Although the study was designed to evaluate safety and efficacy, the registry record’s posted primary outcome is a safety measure. It does not report an efficacy estimate in the outcome data.

The phase distinction matters. The combination phase reflects the original randomized treatment groups, while maintenance figures describe participants represented in a later phase. The record does not report the analysis needed to account for selection into maintenance or the protocol amendment. The maintenance counts should therefore not be interpreted as a stand-alone randomized efficacy or safety comparison.

Finally, the trial’s terminated status and the protocol amendment are important context for understanding study conduct. The registry summary attributes the amendment to a sponsor business decision and describes which participants could continue treatment. It does not report that termination was based on a statistical finding, nor does it provide enough information to infer why the decision was made.

13. Why This Trial Matters Statistically

This trial illustrates why a safety result needs more than a list of affected participants. The registry reports counts for serious and non-serious AEs, but these categories may overlap because one participant can have both. Reading them as mutually exclusive totals would misrepresent the endpoint. The record also reports deaths separately, without specifying their relationship to the AE categories.

It also illustrates the importance of treatment phase and analysis population. The safety set includes randomized participants who received at least 1 dose, and the registry gives separate counts for combination and maintenance. A later-phase group is shaped by who reaches or remains in that phase. The study summary further describes treatment discontinuation and possible continuation of amatuximab after a protocol amendment. Those features make it important not to interpret maintenance counts as a fresh randomized comparison.

Statistically, the posted counts are descriptive rather than inferential. Without a reported comparison, uncertainty interval, or analysis plan, readers cannot judge the precision of a treatment difference or assess how missing follow-up was handled. The registry record also does not state the sponsor’s sample-size rationale or provide an efficacy analysis alongside the safety outcome.

These limitations are useful reminders for clinical-trial interpretation: identify the endpoint’s unit, clarify which participants contribute to each result, distinguish descriptive summaries from formal analyses, and keep the trial’s conduct and follow-up context in view. Such distinctions help prevent a count from being mistaken for a causal or definitive comparative conclusion.

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 registry record gives limited detail about how adverse events were collected, classified, graded, or attributed to treatment. It reports serious and non-serious participant counts, but does not describe event-level timing, duration, recurrence, severity grades, or treatment relatedness. The serious-event term percentages are listed without a stated denominator or calculation method.

The outcome timeframe spans baseline up to 3 years, but individual follow-up duration is not reported. The record does not describe missing outcome data, withdrawals, censoring, or sensitivity analyses. The safety analysis set is defined, but the record does not explain whether all randomized participants received study drug or how any exclusions were handled.

Interpretation is further limited by the study’s termination and protocol amendment. The summary describes continued amatuximab treatment for some participants and discontinuation for placebo participants or those already in follow-up. The registry does not report analyses accounting for these changes, or enough information to determine how they affected exposure and observation.

No inferential statistical analysis, confidence interval, or comparative estimate is reported for the primary safety outcome. Details of the randomization procedure, sample-size justification, multiplicity strategy, interim analyses, and statistical analysis plan are not reported in the registry record. The results therefore support a descriptive account of recorded counts, not a precise comparative conclusion.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Study of the Safety and Efficacy of Amatuximab in Combination With Pemetrexed and Cisplatin in Subjects With Unresectable Malignant Pleural Mesothelioma (MPM) — NCT02357147.
• Registry record last updated 2020-03-17; status last verified 2017-02.
• Results first posted 2020-03-17.
• 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

NCT02357147 is a phase 2 randomized, quadruple-masked, parallel-group study sponsored by Morphotek. It compared amatuximab with placebo, each given with pemetrexed and cisplatin during combination treatment, followed by amatuximab or placebo during maintenance. The study enrolled 124 participants and is listed as terminated.

The primary outcome is the number of participants with AEs and SAEs from baseline up to 3 years. The registry reports phase-specific participant counts and deaths, but no inferential analyses for the outcome. It states that the safety set included randomized participants who received at least 1 dose. The study summary describes a sponsor business decision and subsequent protocol amendment that affected treatment continuation and follow-up. The registry record does not report a sponsor sample-size justification, missing-data method, multiplicity plan, or statistical analysis plan.