Entospletinib (ENTO) as Monotherapy and in Combination With Chemotherapy in Japanese Adults: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Entospletinib (ENTO) as Monotherapy and in Combination With Chemotherapy in Japanese Adults (NCT03135028), a non-randomized phase 1 study. The primary outcome is Percentage of Participants With Adverse Events (AEs) and Laboratory Abnormalities Defined as Dose Limiting Toxicities (DLT).

2. Clinical Question

3. Trial Design

This was a phase 1b study of entospletinib in Japanese participants, listed as phase 1 in the registry. It was nonrandomized, unmasked, and sequential. The registry lists enrollment of 9 participants and two treatment groups: ENTO monotherapy for relapsed or refractory hematologic malignancies, and ENTO with cytarabine and daunorubicin for previously untreated AML. Because treatment assignment was not randomized and there was no masked comparison, differences between groups would not have the protection against selection and assessment bias associated with a randomized, blinded design.

For monotherapy, the stated regimen was ENTO twice daily during each 28-day cycle, continuing until treatment discontinuation criteria were met or participants did not experience clinical benefit. For the combination group, the regimen included a 14-day ENTO lead-in in Cycle 0, followed by ENTO with daunorubicin and cytarabine during induction for up to two 28-day cycles. The description also specifies post-remission chemotherapy for at least 2 cycles and up to 4 cycles, but does not fully describe the treatment details for that stage.

The study start date was 2017-05-19, and the primary completion date was 2019-02-26. The status is terminated; the reason for termination is not reported in the registry record. The brief summary identifies safety and tolerability as the primary objective. Secondary outcomes include the percentage of participants with adverse events and laboratory abnormalities not defined as DLT, and plasma concentration of ENTO. Although 3 outcome measures are listed, the third is not identified in the registry information. The registry reports no analyses. Details such as dose-escalation rules, cohort sizes, and any statistical plan beyond the information described 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.

Before assignment: 13 participants were screened.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The DLT Analysis Set included all participants in the Full Analysis Set (all participants who received at least 1 dose of study drug \[ENTO\]) who received at least 21 days of ENTO or experienced a DLT during DLT assessment window.

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: Full Analysis Set included all participants who received at least 1 dose of study drug (ENTO).

6. Primary Endpoint

The registry lists the primary outcome as Percentage of Participants With Adverse Events (AEs) and Laboratory Abnormalities Defined as Dose Limiting Toxicities (DLT), measured over Cycle 1 (28-day cycle).

The primary endpoint is the percentage of participants with adverse events and laboratory abnormalities defined as dose-limiting toxicities (DLTs) during Cycle 1, which is described as a 28-day cycle. A DLT is a safety event meeting specified severity, duration, or treatment-interruption criteria and attributed to ENTO. The definition covers selected Grade 4 non-hematologic toxicities, specified delayed recovery of neutrophil or platelet counts in participants without bone marrow evidence of hematologic malignancy, clinically significant electrolyte abnormalities, liver test abnormalities, infection related to unexpectedly complicated prolonged myelosuppression, and certain persistent toxicities requiring treatment interruption or dose modification.

In early-phase studies, a DLT endpoint is used to characterize acute tolerability within a defined observation period. It gives a structured way to identify events considered sufficiently serious or persistent to count toward dose-limiting toxicity, rather than treating every adverse event as a DLT. The endpoint is specifically tied to attribution to ENTO and to the Cycle 1 assessment window. It does not represent all possible safety outcomes during the full course of treatment.

The registry record gives the endpoint definition and the population rule but does not report the observed DLT percentage or participant count. It also does not report how many participants entered the DLT analysis set. Consequently, the endpoint’s observed frequency and precision cannot be assessed from the posted results.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary endpoint is a participant-level percentage: it asks what proportion of the defined analysis population experienced at least one event meeting the DLT definition during Cycle 1. This type of endpoint is binary for each participant: a participant either meets the DLT criterion within the specified window or does not. A percentage can be useful for describing the frequency of a safety outcome, but its interpretation depends on the denominator, the event definition, and the completeness of follow-up. The registry record does not report the observed DLT numerator or percentage, so no estimate or interval can be discussed for this endpoint.

The DLT definition combines several clinical criteria rather than one single laboratory threshold. It includes selected Grade 4 non-hematologic toxicities, with stated exceptions; specified failure of blood-count recovery in participants without bone marrow evidence of hematologic malignancy; clinically significant electrolyte abnormalities not corrected within 24 hours; liver function test abnormalities not resolving to Grade 2 within 10 days; infection resulting from unexpectedly complicated prolonged myelosuppression; and certain toxicities that remain unresolved after treatment interruption or lead to prolonged suspension or dose reduction. The definition is limited to toxicities attributed to ENTO and assessed during Cycle 1. Events outside those conditions may still be adverse events, but would not necessarily qualify as DLTs under this endpoint definition.

The DLT Analysis Set is defined from the Full Analysis Set. The Full Analysis Set includes participants who received at least 1 dose of study drug (ENTO). The DLT Analysis Set then includes those who received at least 21 days of ENTO or experienced a DLT during the assessment window. This rule allows a participant who experiences a DLT before reaching the exposure-duration condition to be included. The number of participants in either set is not reported in the registry record. The endpoint denominator therefore cannot be reconstructed from the posted information, and the enrolled total should not automatically be treated as the endpoint denominator.

For a binary percentage, uncertainty is generally important, especially when the analysis population is small. A confidence interval expresses a range of values compatible with the observed data under a specified statistical method; it does not remove uncertainty or guarantee that the true frequency lies within the interval. With few participants, a small change in the event count can substantially alter the percentage, and interval estimates can be wide. These are general properties of binary outcomes, not trial-specific calculations. The registry record does not report a confidence interval or the method used to estimate one.

The record lists no analyses. It therefore does not state whether the primary endpoint was to be reported with a particular interval method, whether analyses were descriptive only, or whether any adjustment or subgroup analysis was planned. No statistical analysis plan, sample-size justification, or interim analysis plan is reported in the registry record. The absence of a reported analysis means that the posted safety counts should be read descriptively, not as results of a documented hypothesis test.

Some planning illustrations use the observed effect as a hypothetical target and state assumptions of a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. Such calculations are not the trial’s own design and are not observed power. In this study, allocation was nonrandomized, and the treatment groups represent different clinical settings; equal allocation between two arms does not make them comparable. A planning calculation based on an observed effect is sensitive to the size of that effect and to the assumptions used. If the primary endpoint result is not reported, its observed effect cannot be evaluated from the registry record.

As a general statistical point, over-dispersion matters when outcomes vary more than a model assumes. It can make standard errors too small if a model assumes less variability than the data contain. The primary outcome is a binary participant-level endpoint, and dispersion is not listed for it. The registry record does not describe a model-based analysis of the DLT endpoint, so there is no basis for attributing a particular over-dispersion adjustment to this study.

The displayed safety counts and term-specific percentages answer descriptive questions, not necessarily comparative ones. A rate or percentage depends on the population at risk and the observation period. Without a reported follow-up description for those figures, event timing and exposure duration cannot be established from the record. Likewise, without participant-level information, the serious event, other adverse event, and death counts cannot be assumed to refer to separate people. These are general interpretation cautions for safety summaries, not additional findings about this trial.

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("ENTO 400 mg")
n      <- c(6)
events <- c(0)
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  ENTO 400 mg  6  0  0.0  0.0  45.9  0.0  39.0  0.4  41.0

11. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary safety endpoint and secondary outcomes covering adverse events and laboratory abnormalities not defined as DLT, and plasma concentration of ENTO. It also states that there are 3 outcome measures, but the third is not identified in the registry information. No analyses are reported. The statistical plan, including any hierarchy among outcomes or adjustment for testing multiple outcomes, is not reported in the registry record. As a general matter, examining several outcomes can increase the chance of at least one apparently notable finding when each is tested separately; whether and how that issue was addressed in this study cannot be determined.

The primary DLT result is absent, as are its numerator, denominator, and uncertainty estimate. The DLT Analysis Set definition is described, but the number of participants meeting it is not reported. The posted record also does not describe how missing endpoint observations were handled, whether all participants completed the Cycle 1 assessment window, or whether any participants were excluded from a particular analysis. The reason for termination is not reported in the registry record, and no further explanation of missing results is available.

The registry defines the Full Analysis Set as participants who received at least 1 dose of ENTO and defines the DLT Analysis Set using exposure duration or occurrence of a DLT. It does not report participant counts for those populations or provide a detailed accounting of participants by group and outcome. Consequently, the relationship between enrollment, treatment exposure, and each posted safety denominator cannot be fully evaluated. These omissions limit assessment of missingness, outcome completeness, and the potential influence of participants not represented in an endpoint 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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: anaemia (11.1%), cataract (11.1%), choroidal haemorrhage (11.1%), pyrexia (11.1%), hepatic function abnormal (11.1%).

For the ENTO 400 mg group, the registry reports 9 participants at risk for serious adverse events, with 4 affected; it reports 9 at risk for other adverse events, with 9 affected. It also lists 6 deaths. These are descriptive figures. The record does not state whether the serious adverse event and other adverse event counts overlap, whether the deaths occurred during treatment or follow-up, or whether any event or death was considered related to study treatment. They should not be interpreted as a causal comparison.

The serious adverse event terms listed are Anaemia, Cataract, Choroidal haemorrhage, Pyrexia, Hepatic function abnormal, and Clostridium difficile colitis, each with a reported percentage of 11.1%. The registry record does not give further detail about timing, duration, outcome, or the basis for attributing these terms to treatment. These term-level percentages are not the primary DLT result: DLTs had a separate definition, attribution requirement, and Cycle 1 timeframe. The observed DLT frequency is not reported in the registry record.

Safety summaries depend on their denominator, event definition, and observation period. The reported counts should therefore be read within the limits of the registry’s definitions rather than as complete descriptions of each participant’s course.

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

The registry record documents a phase 1b evaluation of ENTO monotherapy and ENTO with chemotherapy in Japanese participants, with safety and tolerability as the primary objective. It gives the DLT criteria and reports several safety counts for the ENTO 400 mg group. Those details identify the kinds of events monitored and provide a limited descriptive account of reported adverse events and deaths.

The record does not report the primary DLT outcome. It also does not report an inferential analysis, confidence interval for that endpoint, or a treatment-effect estimate. Thus the frequency and precision of Cycle 1 DLTs cannot be established from the posted information. The safety figures that are available do not, on their own, show that a treatment caused an event or death, nor do they establish a comparative safety difference.

The study was nonrandomized and unmasked, with groups drawn from different clinical settings and receiving different regimens. The monotherapy group concerned relapsed or refractory hematologic malignancies; the combination group concerned previously untreated AML. This structure does not support treating the groups as randomized controls for one another. The registry record does not report a separate control group.

The record also does not establish how results would generalize beyond the participants and settings described, or provide enough detail to reconstruct participant flow through the DLT analysis population. Termination is recorded, but its reason is not reported. These limits mean that the posted information can be used to describe the study design and selected safety records, but not to make a definitive comparative or causal conclusion about treatment effects.

As a general statistical point, an absent estimate is different from an estimate showing no event or no difference. Because the primary result is not reported, the record does not establish that DLTs were absent, nor does it quantify their frequency. The conclusions must remain bounded by the outcomes and analyses that are actually recorded.

14. Why This Trial Matters Statistically

This study is statistically notable for bringing together two distinct early-phase treatment settings under one safety-focused study: ENTO alone for relapsed or refractory hematologic malignancies and ENTO with chemotherapy for previously untreated AML. The study’s nonrandomized, sequential, unmasked design is important context for reading any group-level findings. It describes treatment experience, but does not create a randomized comparison capable of separating treatment effects from differences in participant populations or clinical context.

The primary endpoint is also specific in ways that matter for interpretation. It focuses on DLTs attributed to ENTO during Cycle 1, using a definition that includes particular toxicity grades, laboratory conditions, and duration or treatment-interruption criteria. It is not a general count of all adverse events across the whole treatment course. Keeping that endpoint separate from other adverse event summaries is essential to understanding what each measure can and cannot convey.

The registry’s definition of the DLT analysis population makes exposure and event occurrence relevant to inclusion. Participants qualified after at least 21 days of ENTO or if they experienced a DLT within the assessment window. Since the population size and primary result are not reported, readers cannot assess the endpoint denominator or its precision. This is a concrete example of how a detailed endpoint definition does not by itself establish an interpretable result.

The record also illustrates the distinction between a study’s stated objective and its posted statistical evidence. Safety and tolerability were the stated focus, but the primary endpoint result and analyses are absent. The available counts provide some descriptive safety information, while leaving key questions about attribution, timing, overlap, and analysis populations unresolved. Those limits are consequential when a small study’s results are considered alongside other evidence.

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 most direct limitation is that the registry does not report the primary DLT result. Without the event count and analysis denominator, the primary endpoint’s observed frequency and precision cannot be assessed. The registry reports no analyses, and the reason for termination is not reported. It is therefore not possible to determine from this record whether the missing primary result reflects incomplete reporting, study conduct, or another circumstance.

Enrollment was 9, but the DLT Analysis Set was defined separately from the enrolled population. The number of participants who received at least 1 dose, the number meeting the DLT analysis rule, and the number analyzed in each treatment group are not reported. Participant flow and the handling of missing outcome information are also not described in the registry record.

The study was nonrandomized and unmasked. Its treatment groups involved different populations and regimens, so their safety counts should not be treated as a controlled comparison. The record does not provide an untreated or active-control group, an account of event attribution, or enough detail to determine overlap between serious adverse events, other adverse events, and deaths.

The serious adverse event terms are presented with percentages but without further detail on timing, duration, outcome, or event-level context. The registry’s account of the combination regimen does not fully describe the post-remission treatment details. The statistical plan, sample-size justification, interim analyses, and multiplicity approach are not reported in the registry record. Together, these gaps limit both statistical interpretation and assessment of how complete the posted safety description is.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Entospletinib (ENTO) as Monotherapy and in Combination With Chemotherapy in Japanese Adults — NCT03135028.
• Registry record last updated 2020-03-06; status last verified 2020-02.
• Results first posted 2020-03-06.
• 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

NCT03135028 is a phase 1b study, listed as phase 1, of ENTO monotherapy and ENTO with chemotherapy in Japanese participants. It was nonrandomized, unmasked, and sequential, with 9 participants enrolled. The study began on 2017-05-19, reached primary completion on 2019-02-26, and is listed as terminated.

The primary objective was safety and tolerability. The primary endpoint was the percentage of participants with DLTs during Cycle 1, defined as a 28-day cycle. The endpoint criteria and DLT analysis population are described, but the observed DLT result and analysis population size are not reported in the registry record. No analyses are listed.

The ENTO 400 mg safety record lists 4 participants with serious adverse events among 9 at risk, 9 with other adverse events among 9 at risk, and 6 deaths. The listed serious adverse event terms each have a reported percentage of 11.1%. The record does not establish event attribution or the overlap among these categories. The reason for study termination is not reported in the registry record.