Pinometostat With Standard Chemotherapy in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia and MLL Gene Rearrangement: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Pinometostat With Standard Chemotherapy in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia and MLL Gene Rearrangement (NCT03724084), a non-randomized phase 1, phase 2 study. The primary outcome is Dose Limiting Toxicity (Phase Ib).

2. Clinical Question

The clinical question is whether a pinometostat-containing regimen can be evaluated for dose-limiting toxicity in this population, alongside standard induction chemotherapy. This is a safety and dose-finding question, not a randomized test of the regimen against another treatment. The registry record describes Cohort I as receiving a higher pinometostat dose followed by a lower dose, and Cohort II as receiving a higher dose throughout the described treatment period. Both cohort descriptions include daunorubicin hydrochloride and cytarabine.

The broader study description mentions how well the combination works, and lists outcomes including minimal residual disease positivity, progression-free survival, and overall survival. Those listed outcomes do not establish that comparative efficacy was demonstrated. The record reports no analyses, and the primary endpoint result is not reported in the registry record. The posted information therefore does not answer whether the combination improves outcomes relative to another regimen, nor does it establish an optimal dose. It describes the trial question, the two treatment cohorts, and limited safety counts from a small, non-randomized study.

3. Trial Design

This is a phase 1b/2, non-randomized, single-group study with no masking. Although the record describes two cohorts, allocation is listed as non-randomized; those cohorts should not be interpreted as randomized treatment arms or as a controlled comparison. Enrollment was 6. The study started on 2019-04-10, had a primary completion date of 2022-11-14, and is listed as terminated.

The phase Ib primary endpoint is dose-limiting toxicity, counted as participants, with a timeframe of up to 35 days. The endpoint description says dose escalation for phase 1b will be in the usual 3+3 fashion. The record does not give further operational details about the escalation decisions or how the cohorts were assigned. It describes one cohort receiving higher-dose pinometostat on days 1-7 followed by lower-dose pinometostat on days 8-35, and another receiving higher-dose pinometostat on days 1-35. Both descriptions include daunorubicin hydrochloride on days 8-10 and continuous cytarabine on days 8-14. The record says cycles repeat every 35 days, but the second cohort description is truncated after the wording about disease progression or unacceptable toxicity; the complete stopping rules are not reported in the registry record.

There are 8 outcome measures listed, including adverse events, time to hematologic count recovery, differential blast counts, minimal residual disease positivity, progression-free survival, and overall survival. The record reports 0 analyses. As a result, the cohort schedules and outcome list describe intended study features, but they do not supply analyzed clinical outcome estimates. The termination status and enrollment count provide context for the limited posted evidence; the reason for termination is 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

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 Dose Limiting Toxicity (Phase Ib), measured over Up to 35 days.

The primary endpoint is dose-limiting toxicity in phase Ib. It is defined as a count of participants and has a timeframe of up to 35 days. A dose-limiting toxicity endpoint is used in early-phase research to identify clinically important toxicities that may constrain dose selection. In general, dose-finding studies use safety observations to guide decisions about whether a dose or schedule merits further study. That general role does not establish what dose was selected in this study.

The registry description says escalation will follow the usual 3+3 fashion, but the record does not report the detailed toxicity criteria, decision rules, or dose-limiting toxicity count for either cohort. The primary endpoint result is therefore not reported in the registry record. The listed adverse-event counts are related safety information, but they are not a substitute for the specific primary endpoint: the record does not identify those counts as dose-limiting toxicities within the stated timeframe.

Because the endpoint is a participant count, it is naturally interpreted as the number of participants meeting the endpoint definition, rather than as a continuous measurement. The count needs the endpoint definition, assessment window, and analyzed population to be interpretable. Those details are not fully reported in the registry record. Without an analyzed result and its denominator, no conclusion about the frequency of dose-limiting toxicity or the acceptability of a dose can be drawn from the primary endpoint listing alone.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What kind of study is described?

The record identifies a phase 1b/2 study, with non-randomized allocation, no masking, and a single-group model. In general, randomization helps balance measured and unmeasured characteristics across treatment groups, while masking can reduce some forms of assessment or reporting bias. Neither feature is listed for this study. The two cohorts have different pinometostat schedules, but the record explicitly does not describe a randomized, like-for-like comparison. Any contrast between them would therefore be descriptive rather than a causal treatment comparison.

The record lists a total enrollment of 6 and two cohorts of 3 participants each in the safety entries. With such limited numbers, each participant’s outcome contributes substantially to the observed count. In general, small samples yield imprecise estimates and make it difficult to distinguish a stable pattern from chance variation. No confidence intervals or inferential analyses are posted in the registry record.

How should a participant count be read?

The primary outcome is a count of participants with dose-limiting toxicity within the stated timeframe of up to 35 days. A count is not an event rate unless its denominator and analysis population are also specified. The record gives the endpoint unit and timeframe but does not report the primary count or identify the population used in an analysis. The adverse-event entries include group counts, but those should not be substituted for the primary endpoint because the record does not state that they represent dose-limiting toxicity.

In general, a confidence interval expresses the range of values compatible with the data and a stated statistical procedure. It communicates precision as well as the estimate. For a sparse count, a confidence interval would generally be broad, but no interval for the primary endpoint or serious adverse events is reported. No interval should be inferred from the posted counts.

What does the 3+3 description establish?

The endpoint description says phase Ib dose escalation will use the usual 3+3 fashion. In general, a 3+3 approach is a rule-based dose-escalation framework that evaluates toxicity in small groups at a dose level and uses prespecified rules to guide escalation or de-escalation. The record does not report the actual dose levels, toxicity criteria, complete decision rules, or decisions made during this trial. The general description therefore identifies the approach named in the record, but it is not enough to reconstruct the study’s dose-escalation path.

How should safety counts be interpreted?

Serious adverse-event counts describe the number of participants recorded as affected, not necessarily the number of distinct events. A participant may experience more than one event, and a count of affected participants does not convey event duration, recurrence, severity beyond the serious classification, or causal attribution. The registry’s serious-event entries report affected and at-risk participants by cohort. The record does not provide the event-level detail needed to assess those additional features.

In general, safety reporting should distinguish serious events from dose-limiting toxicities and from all adverse events. The categories answer different questions and may use different definitions. The posted record lists a separate “other” adverse-event count as well as serious-event counts, but does not define the relationship between those categories in enough detail to interpret their overlap. The listed top serious term is reported as 100.0%; its denominator is not identified in the registry record.

What do the planning illustrations mean?

Planning illustrations based on an observed effect are not observed trial outcomes and are not observed power. In general, such calculations ask how many participants might be needed under stated assumptions to detect a specified effect with a chosen error rate and power. Their interpretation depends on the assumed effect, statistical model, allocation, and outcome distribution. The assumptions described for the planning illustrations specify a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. For time-to-event outcomes, the illustration is based on a total event count; for other outcomes, it is expressed as participants per arm.

The study itself is non-randomized and does not provide a like-for-like control comparison, so a two-arm planning illustration should not be mistaken for the trial’s actual design. The record does not provide analyzed treatment effects from which to assess the stability or clinical relevance of an observed effect. No planning number can supply the missing primary endpoint result, make the cohort comparison causal, or show that the trial had adequate enrollment for its intended questions.

Finally, the record reports 0 analyses. Thus, the posted information supports description of the design and the listed safety counts, but not a reconstruction of a statistical analysis plan or an independent reanalysis of endpoint effects. The statistical plan, handling of missing data, analysis populations, and details of any interim analyses are not 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("Cohort I (Higher and Lower Dose Pinometostat)", "Cohort II (Higher Dose Pinometostat)")
n      <- c(3, 3)
events <- c(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  Cohort I (Higher and Lower Dose Pinometostat)  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  Cohort II (Higher Dose Pinometostat)  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists 8 outcome measures, including the primary dose-limiting toxicity endpoint and secondary safety, hematologic recovery, blast count, minimal residual disease, progression-free survival, and overall survival outcomes. It reports 0 analyses. A list of outcomes alone does not show which analyses were conducted, which outcome was emphasized, or how multiple outcomes were handled. The statistical plan, including any multiplicity strategy, is not reported in the registry record.

In general, multiplicity matters when several outcomes or comparisons are tested because repeated testing can increase the chance of a false-positive finding. Possible approaches depend on the study objectives and analysis plan, but no approach should be attributed to this trial without documentation. No adjustment, hierarchy, or prespecified testing sequence is reported in the registry record.

Missing-data handling is also not reported in the registry record. The record does not say how participants with incomplete safety assessments, early discontinuation, or unavailable follow-up were treated in analyses. It does not specify analysis populations, such as whether outcomes were evaluated in all enrolled participants or a subset. These omissions matter because denominators and follow-up completeness affect the interpretation of counts and time-to-event outcomes.

The record does not report interim analyses or stopping rules beyond the brief dose-escalation description. It also does not state whether the listed secondary outcomes were fully assessed or why the study was terminated. These details should be treated as unknown rather than inferred from the outcome list or status.

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: white blood cell decreased (100.0%).

The registry reports serious adverse events in 3 of 3 participants in Cohort I and 1 of 3 participants in Cohort II. Deaths are listed for 2 participants in Cohort I and 1 participant in Cohort II. These are descriptive counts for a study with enrollment of 6; they are not randomized comparisons, and the cohort schedules cannot be compared as though assignment were controlled.

The counts do not establish that treatment caused an event or death. The record does not report attribution, event timing, duration, recurrent events, or the clinical circumstances surrounding deaths. It also does not state whether serious adverse events met the definition of dose-limiting toxicity. Those primary endpoint results are not reported in the registry record.

White blood cell decreased is listed as a top serious adverse-event term at 100.0%, but the denominator behind that percentage is not identified in the registry record. The record separately lists other adverse events affecting all 3 participants in each cohort; the categories and their overlap are not fully explained. These sparse safety entries describe recorded events, not a precise estimate of risk or a comparison of treatment schedules.

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

The record establishes that a phase 1b/2 study of pinometostat with standard induction chemotherapy was conducted in newly diagnosed acute myeloid leukemia with MLL rearrangement. It describes two non-randomized dosing cohorts, reports enrollment of 6, and lists the study status as terminated. It also provides cohort-level counts of serious adverse events and deaths. Those details are useful for understanding the scope and limits of the posted record.

The record does not establish how often the primary endpoint occurred. The dose-limiting toxicity result is not reported in the registry record, and the posted serious adverse-event counts cannot be treated as that endpoint. The record also does not provide analyses for the listed efficacy and follow-up outcomes. It therefore does not establish an effect on disease response, minimal residual disease, progression-free survival, or overall survival.

Because allocation was non-randomized and there was no like-for-like control group, differences between the two cohort descriptions cannot isolate the effect of pinometostat dose or schedule. The study does not provide a direct comparison with standard chemotherapy alone. The available counts also do not identify whether adverse events or deaths were related to study treatment.

In general, a study can contribute useful descriptive safety information without answering a comparative efficacy question. Precision depends on the amount and completeness of data, and a small enrollment limits how much can be learned from the observed counts. The registry record does not report the reason for termination, complete follow-up, or the detailed analysis methods. Conclusions beyond the stated design and posted counts would require evidence not reported in the registry record.

14. Why This Trial Matters Statistically

Statistically, this study is notable for the distinction between a dose-finding question and a comparative treatment question. The phase Ib endpoint focuses on dose-limiting toxicity, and the record describes escalation in the usual 3+3 fashion. That design feature is intended to inform safety and dose selection; it does not by itself estimate whether a regimen improves outcomes relative to a control treatment.

The record also illustrates why cohort labels should not be mistaken for randomized arms. The cohorts follow different pinometostat schedules, but allocation is non-randomized and the study model is single-group. As a result, the serious adverse-event counts are best read descriptively. They cannot establish that one schedule produces more or fewer events than the other.

Enrollment of 6 underscores how limited the posted counts are for estimating uncommon or variable outcomes. Even when every participant is accounted for in a simple count, the estimate can remain imprecise. Here, the primary dose-limiting toxicity result and analyses of the listed secondary outcomes are not reported in the registry record. That absence limits both clinical interpretation and statistical assessment.

The study is also a reminder that a broad outcome list is not the same as a complete report of results. The record lists safety and efficacy-related outcomes but reports 0 analyses. Without estimates, denominators, follow-up details, or an analysis plan, readers cannot judge the precision of outcome effects or how multiple endpoints were treated. The posted information can describe what the study set out to examine and some safety counts, but it does not support stronger comparative conclusions.

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 limitation is the very small enrollment: 6 participants across two non-randomized cohorts. The safety counts are therefore descriptive and provide limited precision. A comparison between the cohorts would be vulnerable to differences unrelated to the pinometostat schedules, and the record does not describe a randomized control group receiving standard chemotherapy alone.

The primary endpoint is identified, but its result is not reported in the registry record. The detailed dose-limiting toxicity criteria, actual escalation decisions, and full dose levels are also not reported. Although the record gives serious adverse-event and death counts, it does not report event attribution, timing, duration, or whether these events met the dose-limiting toxicity definition. The percentage attached to the top serious adverse-event term has no identified denominator in the record.

The study status is terminated, but the reason for termination is not reported in the registry record. The record does not report whether all enrolled participants completed treatment or follow-up, how missing data were handled, or which analysis populations were used. It lists secondary outcomes but reports 0 analyses, leaving their results and precision unavailable. The statistical plan, multiplicity handling, interim analyses, and sample-size justification are not reported in the registry record. These limitations prevent assessment of efficacy, outcome completeness, or the intended statistical operating characteristics.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Pinometostat With Standard Chemotherapy in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia and MLL Gene Rearrangement — NCT03724084.
• Registry record last updated 2025-06-18; status last verified 2025-06.
• Results first posted 2024-06-11.
• 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 phase 1b/2, non-randomized study evaluated pinometostat with standard induction chemotherapy in newly diagnosed acute myeloid leukemia with MLL rearrangement. It enrolled 6 participants, started on 2019-04-10, reached primary completion on 2022-11-14, and is listed as terminated. The two described cohorts used different pinometostat schedules alongside daunorubicin hydrochloride and cytarabine.

The primary phase Ib endpoint was dose-limiting toxicity, measured as participants up to 35 days. The record reports 0 analyses, and the primary endpoint result is not reported in the registry record. Serious adverse events were recorded in 3 of 3 participants in Cohort I and 1 of 3 in Cohort II; deaths were listed for 2 and 1 participants, respectively. These counts are descriptive and do not establish treatment causality or a comparative effect. The reason for termination, detailed analysis methods, and results for listed secondary outcomes are not reported in the registry record.