A Study of E6201 for the Treatment of Advanced Hematologic Malignancies With FLT3 and/or Ras Mutations: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study of E6201 for the Treatment of Advanced Hematologic Malignancies With FLT3 and/or Ras Mutations (NCT02418000), a non-randomized phase 1, phase 2 study. The primary outcome is Number of Participants Who Experienced Dose-Limiting Toxicities (DLTs).

2. Clinical Question

3. Trial Design

This was a Phase 1/2a, nonrandomized, unmasked, sequential study sponsored by Spirita Oncology, LLC. The registry lists an enrollment of 27. The recorded start date is 2015-04-10, the primary completion date is 2017-06-08, and the current status is terminated. A reason for termination is not reported in the registry record.

The brief summary describes a Phase 1 safety run-in, with up to 30 subjects, to establish a recommended Phase 2 dose. The Phase 2a portion was to evaluate three groups of people with relapsed or refractory AML: those with confirmed FLT3 mutation and no prior FLT3 inhibitor exposure; those with confirmed FLT3 mutation and prior exposure; and those with confirmed Ras mutation and no FLT3 mutation. The registry also lists MDS and CMML among the conditions, but does not describe corresponding Phase 2a cohorts in the brief summary.

All listed arms used E6201. The regimens included 240 mg/m^2 IV weekly and 320 mg/m^2 IV weekly, as well as 160 mg/m^2, 240 mg/m^2, and 320 mg/m^2 IV twice weekly. The arm descriptions specify administration over 2 hours on stated days, repeated in 28-day cycles. These are treatment schedules, not randomized assignment groups. The registry does not report the sequence or decision rules used to move between dose cohorts, beyond the stated DLT-based definition for determining the maximum tolerated dose.

Because allocation was nonrandomized and there was no listed control arm, differences across dose groups cannot be interpreted as unbiased treatment contrasts. The groups may differ in dose, schedule, cohort composition, or other features; the registry record does not provide enough information to assess or adjust for such differences.

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.

Cohort 1: E6201 240 mg/m^2 Weekly

Reasons for not completing this period:

Cohort 2: E6201 320 mg/m^2 Weekly

Reasons for not completing this period:

Cohort 3: 160 mg/m^2 Twice Weekly

Reasons for not completing this period:

Cohort 4: 240 mg/m^2 Twice Weekly

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Full analysis set (FAS): All subjects who were administered any fraction of a dose of study medication

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 Participants Who Experienced Dose-Limiting Toxicities (DLTs), measured over Up to 6 weeks for each dose cohort.

The primary endpoint is the number of participants who experienced dose-limiting toxicities, or DLTs, up to 6 weeks for each dose cohort. The analysis population is described as the full analysis set: subjects who were administered any fraction of a dose of study medication. The endpoint is a count of participants with a DLT, not a count of all toxicity events.

The record defines DLTs as prolonged myelosuppression under the stated leukemia-specific NCI criteria, including marrow cellularity below 5% at least 6 weeks from therapy start without evidence of leukemia; at least Grade 3 non-hematologic toxicity, with specified exceptions for controlled nausea, vomiting, or diarrhea and correctable electrolyte disturbances; at least Grade 3 liver function tests lasting more than 7 days; treatment interruption more than 14 days due to toxicity; or another important medical event.

DLT counts are used in dose escalation to help identify a dose that is not associated with an unacceptable frequency of protocol-defined toxicity. The registry defines the maximum tolerated dose as the dose level below the dose at which at least 2 of 6 patients in a dose cohort experienced a DLT. This is a protocol definition, not a reported finding: the actual DLT counts, dose-level decision, and selected maximum tolerated or recommended Phase 2 dose are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does the primary endpoint count?

The primary endpoint is a binary participant-level outcome summarized as a count: whether each participant experienced a protocol-defined DLT during up to 6 weeks for the dose cohort. A participant can meet the definition through several different types of event, but the endpoint counts participants with DLTs rather than tallying every qualifying event as a separate outcome. The registry record specifies the full analysis set as all subjects administered any fraction of a dose of study medication.

In general, a binary outcome is useful when the research question is whether an event occurred within a defined observation period. Its interpretation depends on a clear event definition, a consistent follow-up window, and a well-described population. The registry gives a detailed DLT definition and observation timeframe, but does not report the observed participant counts or any statistical uncertainty around them.

How does dose escalation relate to DLTs?

The registry states that DLTs were collected to determine the maximum tolerated dose. Its definition places that dose one dose level below the level at which at least 2 of 6 patients in a cohort experienced a DLT. This is a rule for interpreting events across dose cohorts. It should not be mistaken for a result: the record does not identify a cohort that met the stated condition, report the escalation decisions, or name a selected dose.

In general, dose-finding decisions require attention to both the number of observed events and the number of participants who could have experienced them. With small cohorts, a single participant’s outcome can materially change the observed count. The registry gives the rule’s cohort threshold, but not cohort-by-cohort results, the planned escalation sequence, or whether any additional decision criteria were used.

What do the safety counts represent?

The adverse-event record gives, for each dose and schedule group, counts of participants at risk and counts affected by serious and other adverse events, alongside a death count. These values are descriptive. They do not, by themselves, measure a causal treatment effect or establish that E6201 caused an event. Nor do the group counts establish a relative safety ranking: the groups were not randomized, their sizes differ, and the registry does not report an adjusted comparative analysis.

In general, an event count is more informative when its denominator, observation period, event definitions, and handling of repeated events are clear. A participant count with an event differs from an event count because one participant may have more than one event. The registry lists participant counts affected, but does not provide detailed event-level timing or recurrence information in the record summarized by these results. The serious-event terms are listed with percentages, but the record does not specify their denominator in the posted listing. Those percentages should therefore be read as recorded, without inferring a denominator.

What can be inferred from a nonrandomized design?

In general, random allocation helps balance both measured and unmeasured characteristics between groups. This study is explicitly nonrandomized, so its dose and schedule groups are not guaranteed to be comparable. The sequential design also means that treatment groups may reflect different points in the dose-development process. Descriptive differences between groups cannot establish that dose or schedule alone explains differences in outcomes.

The record reports no analyses for the outcome measures. It therefore does not supply model-based estimates, adjusted contrasts, confidence intervals, or hypothesis tests for the primary endpoint. In general, a confidence interval describes the range of values compatible with an estimate under the analysis assumptions, and its width conveys precision. Without a reported estimate and interval, precision for the primary endpoint cannot be assessed.

The registry lists secondary outcomes including overall response rate, duration of response, progression-free survival, overall survival, and pharmacokinetic measures. Their inclusion indicates planned outcome domains in the record, not evidence that results were reported. The registry does not provide analyzed results for these outcomes in this record. No statistical model, censoring method, or missing-outcome procedure for them is reported in the registry record.

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("E6201 240 mg/m^2 Weekly", "E6201 320 mg/m^2 Weekly", "E6201 160 mg/m^2 Twice Weekly", "E6201 240 mg/m^2 Twice Weekly", "E6201 320 mg/m^2 IV Twice Weekly")
n      <- c(7, 10, 3, 3, 4)
events <- c(1, 1, 0, 0, 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  E6201 240 mg/m^2 Weekly  7  1  14.3  0.4  57.9  2.6  51.3  3.2  52.7
ARM  E6201 320 mg/m^2 Weekly  10  1  10.0  0.3  44.5  1.8  40.4  2.3  41.3
ARM  E6201 160 mg/m^2 Twice Weekly  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  E6201 240 mg/m^2 Twice Weekly  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  E6201 320 mg/m^2 IV Twice Weekly  4  0  0.0  0.0  60.2  0.0  49.0  0.5  52.2

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 23 outcome measures and no analyses. It identifies secondary outcomes spanning response, duration and time-to-event outcomes, survival, and pharmacokinetic measures. The presence of multiple outcomes raises a general multiplicity issue: when many hypotheses are examined, the chance of at least one apparently unusual result can increase unless the analysis plan addresses that possibility. The record does not report a multiplicity adjustment, a hierarchy among outcomes, or a prespecified testing strategy. It is not possible to determine from this record whether such procedures were planned or used.

Missing-data handling is not reported in the registry record. For the primary endpoint, the analysis population includes subjects administered any fraction of a dose, but that definition alone does not explain how participants without complete DLT follow-up were handled. The stated endpoint window is up to 6 weeks for each dose cohort; rules for incomplete observation, withdrawal, or unevaluable participants are not reported. These details matter because participants with shorter observation may have less opportunity for a DLT to be recorded.

The record does not provide an analysis population for each secondary outcome, nor does it describe censoring or follow-up rules for duration of response, progression-free survival, or overall survival. It also does not report how missing pharmacokinetic measurements were treated. These omissions mean the reader cannot assess whether missingness may have influenced the posted outcome summaries.

The full analysis set definition is stated for the primary endpoint, but an intention-to-treat population is not described. Because the study was nonrandomized, that term would not resolve the comparability limitations in any case. Further analysis-population definitions, missing-data procedures, and multiplicity methods 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 4% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: sepsis (33.3%), febrile neutropenia (33.3%), dyspnea (33.3%), epiglottitis (33.3%), non-cardiac chest pain (33.3%).

The registry lists five E6201 groups by dose and schedule and reports serious adverse events, other adverse events, and deaths as participant counts. For example, the E6201 240 mg/m^2 Weekly group has 7 participants at risk, 4 affected by serious adverse events, 7 affected by other adverse events, and 3 deaths listed. The other groups have their own at-risk denominators and counts; the figures describe each group rather than a randomized comparison.

The listed serious adverse event terms are Sepsis, Febrile neutropenia, Dyspnea, Epiglottitis, Non-cardiac chest pain, and Pyelonephritis, each recorded as 33.3%. The registry listing does not explain the denominator for these percentages, so they should not be converted into participant counts or interpreted as percentages of all 27 enrolled participants. The record also does not establish whether these terms were judged related to E6201.

Death counts are presented separately, but cause, timing, and attribution are not reported in the registry record. In general, safety counts are descriptive and need context on exposure duration, event definitions, and population. As the groups were nonrandomized, their counts do not support a like-for-like comparison of safety between regimens.

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

The registry record establishes that E6201 was evaluated in a sequential Phase 1/2a study of advanced hematologic malignancies with FLT3 and/or Ras mutations. It also states that the primary safety objective involved counting participants with DLTs and using those counts in dose-finding. The primary endpoint results, however, are not reported in the registry record, so the record cannot show whether the DLT-based objective was met or what dose was selected.

The adverse-event information provides descriptive counts for five dose and schedule groups. These counts document that adverse events and deaths were recorded, but they do not establish a causal relationship to treatment. They also do not show that one schedule is safer or less safe than another. Nonrandomized assignment, differing group sizes, and the absence of adjusted comparisons prevent a controlled contrast.

The registry lists response, survival, and pharmacokinetic outcomes as secondary measures, but does not report their analyzed results in this record. Thus, the record does not establish an estimate of antitumor response, duration of response, progression-free survival, overall survival, or pharmacokinetic exposure. The absence of reported results is not evidence that an outcome did or did not occur.

The study status is terminated, but the reason for termination is not reported in the registry record. The record also does not state whether termination was related to safety, efficacy, recruitment, operational considerations, or another cause. Such explanations should not be inferred from status alone.

Overall, the posted information supports a description of study design, the stated DLT definition, and the listed safety counts. It does not support conclusions about efficacy, a recommended dose, comparative effects across groups, or the cause of reported deaths and adverse events. Those questions require results and context not reported in the registry record.

14. Why This Trial Matters Statistically

This study illustrates a common statistical challenge in early-phase research: the main objective is dose characterization, not a randomized comparison of clinical benefit. The registry links the primary endpoint to a DLT-based maximum tolerated dose definition. That makes the event definition, follow-up window, cohort membership, and escalation decisions central to interpretation. Although the endpoint rule is described, the record does not report the DLT counts needed to see how it was applied.

The design is sequential and nonrandomized, with multiple dose levels and weekly or twice-weekly schedules. This structure is relevant because differences among groups may reflect more than dose. Cohort composition and the sequence of enrollment can affect descriptive event patterns, while small groups can make counts sensitive to individual outcomes. The registry reports differing group sizes, but no adjusted comparisons.

The record also shows why enrollment totals should not be mistaken for adequate information about every outcome. It lists 27 enrolled participants and multiple outcome domains, yet reports no analyses for the outcomes. Without endpoint estimates and their uncertainty, readers cannot gauge precision or determine whether the study addressed its planned questions.

Finally, the safety listing separates serious and other adverse events and gives deaths by group, but does not provide attribution or a randomized control. These features make clear distinctions important: recorded events are not automatically treatment-caused events, and descriptive counts are not comparative effects. The statistical value of the registry record is therefore chiefly in defining the study’s structure and intended safety endpoint while making the limits of the available results apparent.

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 registry record does not report the primary DLT counts, a dose-escalation conclusion, or a recommended Phase 2 dose. It also does not report analyzed results for the listed secondary outcomes. Consequently, conclusions about dose selection, response, survival, or pharmacokinetics cannot be drawn from the record.

The trial was nonrandomized, unmasked, and sequential. There is no listed control group, and dose and schedule groups are not described as randomized or otherwise comparable. Descriptive differences across these groups may reflect differences in participants or study conduct as well as treatment regimen. No adjusted comparative analyses are reported.

Although the registry lists an overall enrollment of 27, it does not give the allocation of participants across the Phase 1 and Phase 2a portions or explain how enrollment was distributed among the dose groups and disease cohorts. The brief summary describes the Phase 1 portion as allowing up to 30 subjects, but does not explain the relationship between that planned upper limit and the recorded enrollment.

For safety, the registry gives group-level participant counts, serious adverse event terms, and death counts. It does not report event timing, duration of exposure, causal attribution, or the denominator underlying the percentages attached to the serious-event terms. The reason for termination is also not reported in the registry record. Missing-data procedures, analysis details, and multiplicity handling are not reported, limiting assessment of how outcomes were analyzed and how much uncertainty surrounds them.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Study of E6201 for the Treatment of Advanced Hematologic Malignancies With FLT3 and/or Ras Mutations — NCT02418000.
• Registry record last updated 2019-03-20; status last verified 2019-03.
• Results first posted 2019-03-05.
• 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

This is a nonrandomized, unmasked, sequential Phase 1/2a study of E6201 in advanced hematologic malignancies with FLT3 and/or Ras mutations. The registry records 27 participants, a start date of 2015-04-10, a primary completion date of 2017-06-08, and terminated status. The primary endpoint is the number of participants experiencing DLTs up to 6 weeks for each dose cohort, with the full analysis set defined as subjects administered any fraction of a study medication dose.

The registry describes weekly and twice-weekly E6201 regimens across several dose levels and gives adverse-event and death counts by group. It does not report primary endpoint results, analyses of the listed secondary outcomes, or the reason for termination. Because the design is nonrandomized and no control arm is listed, the safety counts are descriptive rather than controlled treatment comparisons.