Phase 2 Etirinotecan Pegol in Refractory Brain Metastases & Advanced Lung Cancer / Metastatic Breast Cancer: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Phase 2 Etirinotecan Pegol in Refractory Brain Metastases & Advanced Lung Cancer / Metastatic Breast Cancer (NCT02312622), a non-randomized phase 2 study. The primary outcome is Central Nervous System (CNS) Disease Control Rate (Cohort A and C).

2. Clinical Question

In practical statistical terms, the study was intended to describe disease control in selected cancer cohorts receiving the investigational drug, rather than estimate a randomized treatment contrast. The registry lists a planned enrollment of 27, but does not report a primary endpoint result alongside that figure. As a result, the record supports describing the design and endpoint definition, but not estimating the observed disease-control rate or its precision.

3. Trial Design

This was a phase 2, non-randomized, unmasked, parallel study with planned enrollment of 27. It is marked completed. The record gives a start date of 2015-08 and primary completion date of 2018-09-08. It lists three cohorts: NSCLC, SCLC, and metastatic breast cancer involving the brain. All received pegylated irinotecan; there was no placebo or alternative-treatment arm described.

The treatment description specifies an intravenous infusion over 90 minutes every 21 days, in the absence of disease progression or unacceptable toxicity. The cohort descriptions are not identical populations: Cohort A is NSCLC, Cohort B is SCLC, and Cohort C is metastatic breast cancer. The registered primary endpoint is CNS disease control at 12 weeks, with Cohort B stated to be excluded from that outcome. This arrangement means the outcome population and the overall set of enrolled cohorts should not be assumed to be identical.

Because allocation was non-randomized and the cohorts represent different cancer groups, differences between their observed outcomes would not isolate a treatment effect. The registry itself cautions against treating the arms as like-for-like controls. The record does not report a concurrent control group, a random allocation procedure, or masking.

The registry lists 10 outcome measures, including response, disease control, progression-free survival, and overall survival outcomes across the cohorts. It lists zero analysis entries. That does not establish that no analyses were conducted; it means the registry record does not contain analysis entries. The statistical analysis plan, cohort-specific analysis populations, and sample-size justification are 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.

Overall Study

Analysis population for the primary outcome, as defined in the registry: Cohort B (metastatic small cell lung cancer, SCLC) is excluded per protocol from this outcome.

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 Central Nervous System (CNS) Disease Control Rate (Cohort A and C), measured over At 12 weeks.

The primary endpoint is CNS disease-control rate at 12 weeks. Disease control is defined as complete response, partial response, or stable disease. The registry describes reporting this endpoint as a count and percentage of participants who achieve disease control, without a dispersion measure. The primary endpoint title names Cohorts A and C; the population description states that Cohort B, the SCLC cohort, is excluded.

The response definitions use changes in target lesions and clinical status. Complete response requires disappearance of all target lesions sustained for at least 4 weeks, with no new lesions and a stable or improved clinical condition. Partial response requires at least a 30% decrease in target lesion longest diameter, no new lesions, and the same duration and clinical-condition requirements. Progressive disease includes specified tumor growth, new lesions, non-target progression, or clinical deterioration. Stable disease is defined as neither partial response nor progressive disease. Lesions smaller than 10 mm are considered unchanged unless the sum of longest diameters changes by at least 3 mm.

In general, a disease-control endpoint groups tumor responses that meet a defined threshold with stable disease, rather than counting only tumor shrinkage. It can describe the proportion meeting the protocol's disease-status criteria at the stated assessment time. The registry record does not report the observed count or percentage for this primary endpoint, so it does not show how many participants met the definition or how precise that estimate would be.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The record describes a binary-type primary outcome: each participant either meets the stated disease-control definition at the assessment or does not. The endpoint is reported conceptually as a participant count and percentage. The registry record does not post the observed count, percentage, or an accompanying confidence interval. No additional calculation of the primary endpoint is possible from the reported information.

What does a disease-control proportion represent?

In general, a proportion is the number of participants meeting a defined condition divided by the number assessed for that condition. Its interpretation depends on both the outcome definition and the denominator. Here, disease control includes complete response, partial response, or stable disease under the recorded criteria, and the assessment time is 12 weeks. The endpoint population is not wholly straightforward: its title names Cohorts A and C, while its population text says Cohort B is excluded. The registry record does not clarify this wording further or report the analyzed denominator.

How should response criteria be understood?

The registry's response definitions specify lesion measurements, new lesions, duration, and clinical condition. Complete response requires disappearance of target lesions for at least 4 weeks with no new lesions and a stable or improved clinical condition. Partial response requires at least a 30% decrease in target lesion longest diameter, no new lesions, and the same duration and clinical-condition requirements. Progressive disease can be triggered by lesion growth, changes in T2/FLAIR non-enhancing lesions, new lesions, non-target progression, or clinical deterioration. Stable disease is neither partial response nor progressive disease. These criteria establish what counts as a response category; they do not themselves provide observed results.

The record also notes that a lesion below 10 mm in longest diameter is considered unchanged unless there is at least a 3 mm change in the sum of longest diameters. This is part of the measurement rule, not an observed change in any participant. A threshold-based endpoint depends on consistent assessment and classification. Details of review procedures, assessor training, and missing or unevaluable imaging are not reported in the registry record.

What does a confidence interval add?

In general, a confidence interval expresses the statistical uncertainty around an estimate. For a disease-control proportion, it would help show how much uncertainty remains around the observed rate, especially when the number assessed is limited. It does not correct for bias, make non-randomized cohorts comparable, or guarantee that the result will generalize to other populations. No confidence interval for the primary endpoint is reported in the registry record, so its precision cannot be evaluated.

What does non-randomized allocation mean for analysis?

In general, random allocation helps balance measured and unmeasured prognostic factors between treatment groups. This study is marked non-randomized and does not include a like-for-like control comparison. The cohorts are defined by different cancer types, so a contrast between cohorts would combine differences in disease group with any differences in outcomes. It cannot be interpreted as a randomized estimate of treatment benefit. The registry does not report adjustment methods that might address measured differences, and adjustment would not in itself remove all confounding.

What do the planning assumptions indicate?

The record includes general sample-size planning assumptions: a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the effect to detect described as a fraction of the observed effect. It notes that time-to-event illustrations count total events, while other illustrations count participants per arm. These are planning conventions, not observed trial outcomes. No sample-size illustration values are included in the record, and the planning assumptions are not evidence that the study achieved a particular power. The registry does not report the trial's own sample-size justification or whether the planning assumptions were used in its design.

For time-to-event outcomes, the registry lists progression-free survival and overall survival among secondary outcomes for Cohorts A and C. In general, time-to-event analyses account for both the time until an event and participants who have not experienced the event by their last observation. The record does not report event counts, follow-up distributions, censoring details, survival estimates, or analysis methods for these outcomes. The statistical interpretation of those endpoints therefore cannot be reconstructed from the registry entry.

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("Cohort A - Pegylated Irinotecan to Treat NSCLC", "Cohort C - Pegylated Irinotecan to Treat mBC")
n      <- c(12, 12)
events <- c(2, 2)
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  Cohort A - Pegylated Irinotecan to Treat NSCLC  12  2  16.7  2.1  48.4  4.7  44.8  5.0  45.4
ARM  Cohort C - Pegylated Irinotecan to Treat mBC  12  2  16.7  2.1  48.4  4.7  44.8  5.0  45.4

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 10 outcome measures, including multiple response and disease-control outcomes, progression-free survival, and overall survival. When several outcomes are evaluated, the chance of at least one apparently notable finding can increase if each is tested separately. In general, multiplicity procedures can control specified error rates, but the appropriate approach depends on the prespecified objectives and analysis plan. The registry record does not report a multiplicity strategy, outcome hierarchy, or which outcomes were confirmatory.

The record lists zero analysis entries and does not report p-values or confidence intervals for the primary or secondary outcomes. The analysis plan, including any planned adjustment for multiple testing, is not reported in the registry record. It is therefore not possible to determine whether multiplicity was addressed in analyses conducted outside the registry.

Missing outcome data are another concern for proportion estimates. In general, participants without an evaluable assessment may affect the denominator and the estimated disease-control rate, depending on how they are handled. The registry does not report the number of participants assessed at 12 weeks, missing-data amounts, reasons for missingness, or an imputation or sensitivity-analysis approach. It also does not specify whether the primary analysis used all enrolled participants, only participants with evaluable assessments, or another analysis population.

The registry records planned enrollment and cohort-level safety information, but those figures do not establish the primary endpoint denominator. The endpoint's cohort wording also merits attention: its title names Cohorts A and C, while the population text says Cohort B is excluded. The record does not report how this wording was implemented in the analysis.

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 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: febrile neutropenia (66.7%), diarrhea (33.3%), sepsis (33.3%), dehydration (33.3%), stroke (33.3%).

The safety record reports serious adverse event figures by cohort. For Cohort A, 12 participants were at risk and 12 were reported as affected by serious adverse events. For Cohort B, 3 were at risk and 3 were affected. For Cohort C, 12 were at risk and 6 were affected. These are cohort-specific registry counts; they should not be combined into a single study-wide rate without a clearly defined population and analysis.

The record lists febrile neutropenia at 66.7%, and diarrhea, sepsis, dehydration, stroke, and septic shock each at 33.3% among the top serious event terms. The record does not state the denominator or cohort attribution for these listed percentages in the event-term information, so they should not be assigned to a particular cohort or interpreted as rates for all enrolled participants. The separate other-adverse-event figures are also reported by cohort: 12 of 12 for Cohort A, 3 of 3 for Cohort B, and 12 of 12 for Cohort C.

Deaths are recorded as 11 in Cohort A, 3 in Cohort B, and 11 in Cohort C. The registry record does not establish from these counts whether deaths were caused by treatment, disease, or another cause. Serious adverse event counts describe reporting in the registry; they do not by themselves establish comparative risk or causation. There is no randomized control group for a comparative safety assessment.

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

The record establishes that this was a phase 2 study of pegylated irinotecan in three non-randomized cancer cohorts, with a registered primary endpoint of CNS disease control at 12 weeks. It also provides definitions for complete response, partial response, stable disease, and progressive disease. Those details explain what the study intended to measure.

The record does not report the primary endpoint count or percentage, or an uncertainty interval. It therefore does not show the observed CNS disease-control rate or how precisely it was estimated. The listed secondary outcomes likewise do not establish results when their values are absent. A study's endpoint definitions and treatment schedule are not substitutes for outcome data.

The design also limits what could be inferred from comparisons across cohorts. Participants were not randomly allocated, there was no described control group, and the cohorts differed by cancer type. Differences in outcomes between these groups could reflect differences in disease populations or other factors, rather than the intervention. The record cannot support a causal comparison against an alternative treatment.

The safety counts describe serious adverse event reporting and deaths by cohort, but they do not determine whether the intervention caused any event or death. The listed serious event terms and percentages lack cohort-specific attribution in the event-term listing. No comparative safety group is reported.

In short, the registry record is informative about the trial's design, population categories, treatment administration, and intended outcome definitions. It is not sufficient to judge the magnitude or precision of efficacy outcomes, and it does not establish a treatment effect. Those conclusions would require outcome results and relevant analysis details not reported in the registry record.

14. Why This Trial Matters Statistically

This study illustrates why a registry entry's design and endpoint definitions should be distinguished from its results. A detailed endpoint definition can make clear what qualifies as CNS disease control, including the response categories, lesion measurement rules, and assessment time. But without the observed number meeting that definition, the endpoint cannot be summarized as an estimated rate.

It also highlights the importance of understanding the comparison structure. A non-randomized study with cohorts defined by cancer type does not create a direct treatment comparison simply because the cohorts appear alongside one another. In general, causal contrasts require a design and analysis that address the differences between groups. The registry explicitly cautions that these are not like-for-like control arms.

The record also shows why cohort labels and outcome populations need careful reading. The primary endpoint title identifies Cohorts A and C, while its population description says Cohort B is excluded. Without a reported analysis denominator or outcome value, readers cannot resolve how many participants contributed to the endpoint estimate.

Finally, the entry distinguishes outcome measures from posted analyses. Ten measures are listed, but zero analysis entries appear. This does not prove that no analysis took place; it means registry readers lack posted analysis results in this record. For researchers, this is a useful reminder that a trial's registration, completion status, and endpoint specification are not equivalent to a report of estimated effects, uncertainty, or methods used to handle missing data and multiple outcomes.

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 principal limitation for interpreting efficacy is that the registry record does not report the primary endpoint result. It gives neither the count nor percentage achieving CNS disease control at 12 weeks, and it provides no interval to assess precision. The listed secondary outcomes are not accompanied by results or analysis details.

The primary endpoint description has a population wording issue: the title names Cohorts A and C, whereas the population statement says Cohort B is excluded. The record does not report the analyzed denominator or clarify how the cohort wording was applied. Enrollment is listed as 27, but that number should not be treated as the endpoint denominator.

The study is non-randomized, unmasked, and lacks a described control group. Cohorts represent different cancer types, so comparisons across them would not provide a like-for-like treatment contrast. The registry does not report statistical adjustment methods or details that could support a causal interpretation.

Analysis populations, missing-data amounts and handling, multiplicity procedures, and the statistical analysis plan are not reported in the registry record. Although the record lists 10 outcome measures, it lists zero analysis entries. Safety information includes cohort-specific counts, but the record does not provide a comparative control group or causal attribution for deaths and serious adverse events. These gaps limit assessment of both the magnitude and reliability of the study's outcomes.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Phase 2 Etirinotecan Pegol in Refractory Brain Metastases & Advanced Lung Cancer / Metastatic Breast Cancer — NCT02312622.
• Registry record last updated 2023-12-12; status last verified 2023-11.
• Results first posted 2019-09-10.
• 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.

19. Record Summary

NCT02312622 is a completed phase 2, non-randomized, unmasked, parallel study of pegylated irinotecan in NSCLC, SCLC, and metastatic breast cancer involving the brain. The registry lists planned enrollment of 27, a start date of 2015-08, and primary completion on 2018-09-08. Treatment was described as an intravenous infusion over 90 minutes every 21 days in the absence of disease progression or unacceptable toxicity.

The primary outcome is CNS disease control at 12 weeks, defined as complete response, partial response, or stable disease. The endpoint title names Cohorts A and C, and the population description excludes Cohort B. The registry record does not report the primary endpoint value or analysis results. It lists 10 outcome measures and zero analysis entries. Because the cohorts were not randomized and were different cancer groups, they do not provide a like-for-like control comparison. The record also lists serious adverse event counts by cohort, but does not establish causation or comparative safety.