Management of Severe Chemotherapy-induced Neutropenia in Advanced Breast Cancer: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Management of Severe Chemotherapy-induced Neutropenia in Advanced Breast Cancer (NCT03104595), a non-randomized phase 1, phase 2 study. The primary outcome is Duration of Grade 4 Neutropenia.

2. Clinical Question

The central statistical question is descriptive: what duration of severe neutropenia was recorded during the specified treatment cycle in each dose cohort? The trial's stated aim was to assess safety and establish a dose for assessing pharmacokinetic activity. It was not described as a randomized efficacy comparison. The registry lists febrile neutropenia and Grade 3-4 neutropenia among its secondary outcomes, but their outcome results are not reported in the registry record.

Because the study is non-randomized and sequential, the dose cohorts should not be treated as interchangeable groups differing only in dose. Cohort comparisons may be useful for describing the record, but do not by themselves establish that a dose caused a difference in neutropenia duration. The registry record does not report a concurrent control group or an adjusted comparison between cohorts.

3. Trial Design

This is a Phase 1/Phase 2, non-randomized, open-label, sequential dose-escalation trial of EC-18. The registry lists an enrollment of 28. Participants were assigned to cohorts receiving EC-18 at 500 mg, 1000 mg, 1500 mg, 2000 mg, 3000 mg, or 4000 mg. All listed cohorts are EC-18 dose groups; no placebo or usual-care arm is described.

The registry record gives the study start as 2017-10-30 and the primary completion date as 2019-11-26, with the study status recorded as completed. The stated population was patients with advanced breast cancer receiving chemotherapy with low febrile-neutropenia risk who were candidates for second-line or higher combination therapy with doxorubicin and cyclophosphamide. The registry describes the study purpose as assessing safety and establishing a dose for assessing pharmacokinetic activity following EC-18 administration.

Sequential allocation means the cohorts were not formed through random assignment. Open-label means masking was not used. These design features matter when interpreting differences across dose groups: observed cohort differences can be described, but the design does not provide the protections of a randomized, masked comparison. The registry record does not report further details about the escalation rules, dose selection decisions, or whether any other factors were considered when moving between cohorts.

The primary endpoint was duration of Grade 4 neutropenia during Cycle 1 of chemotherapy, with a stated timeframe of up to 21 days. The registry describes the measure as a mean with standard deviation and identifies absolute neutrophil count assessed using NCI CTCAE v4.03. Although seven outcome measures are listed, analyses are not reported in the registry record. The primary endpoint's cohort values and the results for the secondary outcomes are also 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: Before participating in this clinical study, the subject or his/her legal representative was fully informed of the contents of the clinical study, the effects of the IP, and AEs, before obtaining written and voluntary consent. To protect the subject's privacy, subject records such as every case report forms (CRF) and accountability log of IPs were made available only by the subject's code number and initials.

Overall Study

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.

Only the first 6 of 7 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Duration of Grade 4 Neutropenia, measured over During Cycle 1 of chemotherapy (up to 21 days).

The primary endpoint is the duration of Grade 4 neutropenia during Cycle 1 of chemotherapy, expressed in days. The registry specifies that the timeframe is up to 21 days and that neutropenia is based on absolute neutrophil count assessed using NCI CTCAE v4.03. The planned summary type is a mean with standard deviation.

Duration describes how long a participant meets the endpoint's Grade 4 neutropenia criterion during the specified cycle. It therefore conveys a different feature of the episode from whether Grade 3-4 neutropenia occurred at all. A duration measure can characterize the time course of the condition, while a count of participants with an event describes how many met an event definition. These are distinct kinds of outcome information.

In general, the mean gives a measure of the center of a set of observed durations, and the standard deviation describes how spread out those durations are around the mean. Neither statistic alone shows the full distribution, and neither conveys the precision of the mean in the way a confidence interval would. The registry record does not report the mean, standard deviation, participant-level values, confidence interval, or cohort-specific endpoint results. As a result, the direction and magnitude of any differences in duration across the dose cohorts are not reported in the registry record.

The endpoint is relevant to the study's stated safety focus because it measures the duration of a specified grade of neutropenia within a defined chemotherapy cycle. It should not be interpreted as a direct measure of the broader clinical course beyond that timeframe, or as evidence of a comparative treatment effect.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Statistical interpretation begins by distinguishing the endpoint definition from its results. The registry defines the primary outcome as duration, in days, of Grade 4 neutropenia during Cycle 1, measured using absolute neutrophil count under NCI CTCAE v4.03. It specifies a mean and standard deviation as the summary form. Those details indicate what was intended to be summarized; they are not themselves observed outcome values. The mean and standard deviation are not reported in the registry record.

What does a mean describe?

In general, a mean summarizes the center of measured values by averaging them. For a duration endpoint, it represents the average observed time under the endpoint definition among the observations included in the analysis. It can be useful for comparing descriptive summaries, but it does not reveal whether values cluster tightly or whether a small number of longer durations influence the average. The standard deviation gives a measure of spread around the mean, but does not give the uncertainty of the mean estimate. A confidence interval would address precision, but one is not reported for this endpoint in the registry record.

Since no endpoint estimates or participant-level distributions are reported, it is not possible to assess the shape or variability of the duration data from the registry record. The record does not say whether the analysis used all enrolled participants, only participants with an observed endpoint, or another defined analysis population. It also does not report how duration was defined when an observation was incomplete or how missing measurements were treated.

Why does the design affect interpretation?

In general, random assignment helps balance known and unknown factors between comparison groups. This trial is explicitly non-randomized, and its cohorts received sequential dose levels. The cohort summaries can describe what was recorded in each dose group, but cohort differences cannot automatically be attributed to dose. Other differences between groups, including factors associated with their place in the sequence, could also contribute. The registry record does not report a control arm, masking, covariate adjustment, or a causal comparison between dose levels.

The study is open-label, so masking was not used. This is a design fact, not evidence that measurement was biased. However, when outcome assessment or study conduct could be influenced by knowledge of treatment, the lack of masking is relevant context. The registry record does not report safeguards or assessment procedures beyond identifying ANC and NCI CTCAE v4.03 for the primary endpoint.

What do the planning assumptions mean?

The registry describes sample-size illustrations as planning calculations based on the observed effect, not as the trial's own design. The stated assumptions are a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the effect to detect set as a stated fraction of the observed effect. These are assumptions for illustrative planning, not evidence that the trial used those methods to determine enrollment or conducted a two-arm randomized comparison.

In general, a sample-size calculation estimates how much information a future study might need to detect a specified effect under stated assumptions. It is not an observed result and should not be described as observed power. Here the cohorts were sequential and non-randomized, unlike the equal-allocation two-arm framework used in the planning assumptions. The registry record does not report the protocol's sample-size justification, and the planning illustrations should not be mistaken for the trial's actual design or analysis.

What can be inferred from the posted statistics?

The record lists seven outcome measures and no reported analyses. It does not provide the primary endpoint estimates, an inferential test, confidence intervals, or an adjusted model. General statistical principles can explain what these quantities would mean, but cannot substitute for values that are not reported in the registry record. In particular, the absence of a reported test is not evidence of either a statistically significant or a non-significant finding.

Safety data require similar care. The registry reports numbers at risk and numbers affected by serious and other adverse events within each cohort. These are event summaries, not a comparative model. In general, a count describes the events recorded under the specified reporting framework; its interpretation depends on the population, observation period, and event definitions. The registry record does not provide additional analytic detail on these aspects. The listed safety figures therefore should be read as cohort-specific descriptive information rather than as a causal estimate of dose effects.

10. Confidence Intervals for Each Arm

No two-arm comparison is shown for this trial, but each arm's mean can be given with a t-based 95% confidence interval computed from the posted mean, spread and number of participants.

R code and output

arm <- c("Cohort 1", "Cohort 2", "Cohort 3", "Cohort 4", "Cohort 5", "Cohort 6")
n   <- c(6, 3, 4, 6, 3, 4)
m   <- c(4.8, 6, 4, 4.2, 4.3, 4.8)
sp  <- c(1.9, 2.6, 2.2, 1.3, 1.5, 1.7)
sd  <- sp      # posted standard deviations
for (i in seq_along(n)) {
  se <- sd[i] / sqrt(n[i]); h <- qt(0.975, n[i] - 1) * se
  cat(sprintf("CARM|%s|%d|%.3f|%.3f|%.3f|%.3f\n", arm[i], n[i], m[i], sd[i], m[i] - h, m[i] + h))
}

CARM  Cohort 1  6  4.800  1.900  2.806  6.794
CARM  Cohort 2  3  6.000  2.600  -0.459  12.459
CARM  Cohort 3  4  4.000  2.200  0.499  7.501
CARM  Cohort 4  6  4.200  1.300  2.836  5.564
CARM  Cohort 5  3  4.300  1.500  0.574  8.026
CARM  Cohort 6  4  4.800  1.700  2.095  7.505

11. Multiplicity, Missing Data and Analysis Populations

The registry lists seven outcome measures, including duration of Grade 4 neutropenia as the primary outcome and secondary outcomes for Grade 3-4 neutropenia and febrile neutropenia. It does not report how the outcomes were prioritized for statistical testing, whether any multiplicity adjustment was planned, or whether a hierarchical testing strategy was used. A statistical plan is not reported in the registry record. Without those details and without reported outcome analyses, the impact of testing multiple outcomes cannot be evaluated.

In general, multiplicity arises when several hypotheses or outcomes are tested: the chance of at least one misleadingly positive finding can increase if testing is not accounted for. This general concern does not establish that any finding in this trial is unreliable; the registry record does not report tests or their results. It also does not report interim analyses, so no interim-testing approach should be inferred.

The registry record does not describe missing primary endpoint observations, the number included in an endpoint analysis, or any method for handling missing data. It does not report whether the primary endpoint analysis population was defined in advance or whether participants were analyzed according to a particular inclusion rule. These omissions prevent assessment of whether missingness could have affected the endpoint summaries.

Likewise, no analysis population is specified for the primary outcome in the registry entry. The enrollment figure and the safety-summary denominators do not establish the denominator used for the primary endpoint. They should not be substituted for a reported endpoint analysis population. The record does not report sensitivity analyses addressing missing data or alternative analysis populations.

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 (57.1%), neutropenia (25.0%).

The safety record lists serious adverse events by cohort, with numbers at risk and numbers affected. Cohort 1 lists 7 at risk and 4 affected; Cohort 2 lists 3 at risk and 0 affected; Cohort 3 lists 4 at risk and 1 affected; Cohort 4 lists 6 at risk and 2 affected; Cohort 5 lists 4 at risk and 2 affected; Cohort 6 lists 4 at risk and 1 affected. The record lists 0 deaths for each cohort.

The record also lists numbers affected by other adverse events: 7 of 7 in Cohort 1, 3 of 3 in Cohort 2, 4 of 4 in Cohort 3, 6 of 6 in Cohort 4, 4 of 4 in Cohort 5, and 4 of 4 in Cohort 6. These figures are descriptive counts within the recorded cohorts. They are not randomized comparisons, and the dose cohorts should not be treated as equivalent control groups.

The registry lists Febrile Neutropenia at 57.1% and Neutropenia at 25.0% among the top serious-event terms. The record does not explain the denominator underlying these term percentages or provide additional details about event timing and recurrence. They should therefore be read as the registry's listed percentages, not converted into participant counts or treated as directly comparable risks across cohorts.

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

The registry record establishes what this trial was designed to study: EC-18 in patients with advanced breast cancer receiving low febrile-neutropenia-risk chemotherapy, using a sequential dose-escalation design. It identifies six dose cohorts and defines duration of Grade 4 neutropenia during Cycle 1 as the primary endpoint. It also records cohort-specific serious and other adverse-event counts.

The record does not report the primary endpoint values, so it does not show the average duration of Grade 4 neutropenia in any cohort or the degree of variability in those measurements. It also does not report confidence intervals or statistical tests for the primary endpoint. Consequently, the posted results do not establish the size, direction, or precision of a difference in duration across doses.

The design does not support treating cohort differences as if they came from a randomized comparison. Sequential, non-randomized allocation means that dose and cohort membership are linked; no control group is described. Any observed differences, if available elsewhere, would need to be interpreted in light of these features and would not, by themselves, demonstrate that dose caused the difference.

The safety listings provide descriptive information, but they do not amount to a complete assessment of all possible safety outcomes or establish comparative safety across dose levels. The registry lists Grade 3-4 neutropenia and febrile neutropenia as secondary outcomes, but their results are not reported in the registry record. Absence of posted outcome results should not be interpreted as evidence that an outcome did not occur.

In general, a trial's design and endpoint definition explain what evidence it aimed to produce; observed estimates and their uncertainty are needed to judge what the results show. Here the record permits a description of the study framework and the posted safety counts, but not a conclusion about the primary endpoint's observed pattern or a causal effect of EC-18.

14. Why This Trial Matters Statistically

This trial is statistically notable because it combines sequential dose escalation with a continuous duration endpoint. The design and endpoint answer different parts of the research question: dose cohorts structure the safety assessment, while duration of Grade 4 neutropenia describes how long the specified condition persisted during Cycle 1. Clear interpretation requires keeping the endpoint's measurement scale distinct from event counts such as the number of participants with neutropenia or febrile neutropenia.

The non-randomized design is central to how cohort information can be used. Dose-specific summaries can help describe the record, but they do not carry the same causal interpretation as a randomized comparison. The sequential structure also makes it important to distinguish a pattern across cohorts from evidence that dose alone explains that pattern. The registry record does not report an adjusted analysis that would address other cohort differences.

Another statistical point is the distinction between a mean and its precision. The registry identifies a mean and standard deviation as the primary endpoint summary, but reports neither endpoint estimates nor confidence intervals. A mean would describe the center of observed durations, while a standard deviation would describe spread; confidence intervals would help convey uncertainty about an estimate. Each answers a different question, and none can be recovered from the design description alone.

The record also illustrates why registry outcome listings and outcome results are not interchangeable. Seven measures are listed, yet analyses and primary endpoint values are not reported. The safety summaries remain useful as descriptive records, but they cannot substitute for missing endpoint estimates or a stated analysis plan. Statistically, the most defensible reading separates the study's aims and measurement definitions from results the registry does not report.

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 main trial-specific limitation in interpreting the registry entry is that the primary endpoint results are not reported. Although the endpoint, unit, summary type, and timeframe are specified, the registry does not give cohort means, standard deviations, confidence intervals, or an analysis population. This prevents assessment of the observed duration of Grade 4 neutropenia and its precision.

The study is non-randomized, open-label, and sequential. The six cohorts receive different EC-18 doses, but the record does not describe a control group or a randomized dose comparison. Differences between cohorts therefore cannot be attributed to dose alone. The registry does not report an adjusted analysis, escalation decision rules, or further details about cohort comparability.

The record states enrollment of 28, while its safety summaries report cohort-specific denominators. It does not explain the relationship between enrollment and the population contributing to the primary endpoint, or report any missing primary endpoint data. The safety denominators should not be assumed to be the primary endpoint denominators.

Seven outcome measures are listed, but the registry reports zero analyses. It does not state how multiplicity was handled, provide a statistical analysis plan, identify interim analyses, or explain the sample-size justification. The planning assumptions described in the record are illustrations, not evidence of the trial's own design rationale. These missing details limit assessment of the statistical methods and of how outcomes were selected or interpreted.

The adverse-event entry provides cohort counts and selected serious-event terms, but further information about event definitions, timing, or the denominator for the term percentages is not reported in the registry record. These limitations mean the safety figures should be treated as descriptive registry summaries rather than a complete or comparative safety analysis.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Management of Severe Chemotherapy-induced Neutropenia in Advanced Breast Cancer — NCT03104595.
• Registry record last updated 2026-11-04; status last verified 2023-08.
• Results first posted 2026-11-04.
• 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 describes a completed Phase 1/Phase 2, non-randomized, open-label, sequential dose-escalation trial of EC-18 in patients with advanced breast cancer receiving low febrile-neutropenia-risk chemotherapy. It lists enrollment of 28 and six dose cohorts: 500 mg, 1000 mg, 1500 mg, 2000 mg, 3000 mg, and 4000 mg.

The primary endpoint was duration of Grade 4 neutropenia during Cycle 1, measured in days using ANC assessed under NCI CTCAE v4.03. The intended summary was a mean with standard deviation. The registry record does not report the primary endpoint results or an analysis population. Seven outcome measures are listed, with no analyses reported.

Cohort-specific serious and other adverse-event counts are recorded, along with selected serious-event terms. Because the dose cohorts were not randomized and no control group is described, these safety listings are descriptive rather than like-for-like comparisons. The record does not report a statistical analysis plan, multiplicity approach, or missing-data methods.