An Investigational Immuno-therapy Study of Ulocuplumab in Combination With Low Dose Cytarabine in Patients With Newly Diagnosed Acute Myeloid Leukemia: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for An Investigational Immuno-therapy Study of Ulocuplumab in Combination With Low Dose Cytarabine in Patients With Newly Diagnosed Acute Myeloid Leukemia (NCT02305563), a randomized phase 1, phase 2 study. The primary outcome is Number of Participants With Dose-Limiting Toxicities (DLTs) in Treatment Cycle 1 - Phase 1.

2. Clinical Question

The registry describes a study of safety and effectiveness in newly diagnosed acute myeloid leukemia, but the primary endpoint posted for analysis is a safety count: participants with dose-limiting toxicities during cycle one. It is not an endpoint that directly measures effectiveness. The registry also lists best overall response as a secondary outcome for Phase 1 and several safety and laboratory outcomes for Phase 2.

The central interpretive distinction is between the primary Phase 1 dose-escalation result and the Phase 2 group summaries. The primary outcome is reported for ulocuplumab 600mg plus low dose cytarabine and ulocuplumab 800mg plus low dose cytarabine. The Phase 2 results separately describe participants with adverse events, serious adverse events, and deaths for ulocuplumab 800mg plus low dose cytarabine, ulocuplumab 1000mg plus low dose cytarabine, and low dose cytarabine alone. These outcomes concern different study phases and should not be treated as if they were one common comparison.

For the primary question, the registry reports zero participants with dose-limiting toxicities in each of the two Phase 1 cohorts, each of which had 3 participants. That is a descriptive observation in small cohorts over the specified first-cycle window. It does not, on its own, establish the frequency of such toxicities in a larger population or settle questions about longer-term safety or effectiveness.

3. Trial Design

The registry identifies this as a Phase 1/2, randomized, open-label, parallel study of ulocuplumab in combination with low dose cytarabine in newly diagnosed acute myeloid leukemia. The sponsor is Bristol-Myers Squibb. Enrollment is recorded as 70, and the trial status is terminated. The registry record does not report the reason for termination.

The Phase 1 portion is described as an escalation cohort. Its listed arms are ulocuplumab 600mg plus low dose cytarabine and ulocuplumab 800mg plus low dose cytarabine; the arm description says the Phase 1 cohort was closed for enrollment. The primary outcome is tied to this phase. The Phase 2 portion is described as an expansion cohort and includes ulocuplumab combination groups and a low dose cytarabine-only group. The posted Phase 2 summaries identify the combination groups as 800mg and 1000mg ulocuplumab with LDAC 20mg BID, and the comparator as LDAC 20mg BID.

Although the overall allocation is recorded as randomized, the registry record does not report the randomization procedure, allocation ratio, concealment method, or whether the Phase 1 dose-escalation and Phase 2 expansion components used the same allocation process. Masking is listed as none, so the study is open label. The parallel model indicates that participants were assigned to study arms rather than crossing between treatments, but the registry record does not report further operational detail about the assignment or conduct.

The primary endpoint is assessed from first dose to the end of cycle 1, defined as 28 days. The Phase 2 adverse-event, serious-adverse-event, and death outcomes use a timeframe from first dose until a minimum follow-up of up to 2 months. These different windows matter when interpreting counts: the Phase 1 primary result concerns a specific early treatment period, while the Phase 2 summaries cover a longer and differently specified follow-up period. The registry record does not report a sample-size justification or a detailed statistical analysis plan.

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: 6 participants in Phase 1 and 64 participants in Phase 2 (70 in total) were assigned to treatment. 2 participants randomized to the LDAC-only arm in Phase 2 did not receive treatment. 68 participants in total (phases 1 and 2) were treated.

Treatment Period

Reasons for not completing this period:

Follow-up Period

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: All treated participants

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 With Dose-Limiting Toxicities (DLTs) in Treatment Cycle 1 - Phase 1, measured over From first dose to end of cycle 1 (28 days).

The primary endpoint is the number of participants with dose-limiting toxicities in treatment cycle 1 of Phase 1. It is a count of participants meeting the endpoint, rather than a continuous measurement or a time-to-event estimate. The registry defines the observation window as first dose through the end of cycle 1, which is 28 days.

The registry states that dose-limiting toxicities and other toxicities were defined and evaluated using National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.03. A dose-limiting toxicity was defined based on events considered related to ulocuplumab in combination with low dose cytarabine and occurring during the first cycle of drug administration. Thus, the endpoint combines an event-severity framework with a treatment-relatedness judgment and a fixed early follow-up window.

This type of endpoint is used in early-phase dose evaluation because the occurrence of treatment-limiting toxicity can inform safety assessment during initial exposure. That is a general explanation of the endpoint’s role; the registry record does not report the specific dose-escalation decision rules or how the endpoint influenced later study decisions. It also does not give a separate participant-level breakdown of toxicity types contributing to the primary result.

The posted result is zero participants with dose-limiting toxicities in each listed Phase 1 dose cohort, with 3 participants in each. This count should be read as a finding within the defined cycle-one window and the all-treated population, not as proof that no toxicity occurred: the endpoint counts only events that met the registry’s dose-limiting toxicity definition.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary and secondary outcomes are presented mainly as participant counts: the number meeting a binary event definition within the stated follow-up period. A count is straightforward to understand, but it is tied to the number of participants observed. For interpretation, a count should therefore be read alongside its group size and the endpoint definition, rather than as a stand-alone measure.

What does a risk difference describe?

For the Phase 2 binary comparisons, the recalculated effect measure is the risk difference. In general, a risk difference subtracts the event proportion in one group from the event proportion in the reference group; it is expressed on the absolute probability scale. A value below zero means the event proportion in the comparison group is lower than in the reference group under the stated subtraction convention. It does not by itself indicate a causal treatment effect. Here, the comparison groups are small, and the estimate is subject to sampling uncertainty and the limitations of an unadjusted comparison.

The posted risk-difference results are recalculations from the registry’s group counts. They are not listed as sponsor-reported analyses, and the reported-analyses lists are empty for these outcomes. The registry record does not report adjusted estimates, covariate models, or a prespecified comparison method. Accordingly, the estimates should be described as unadjusted re-calculations, not as the trial’s definitive inferential analysis.

How should confidence intervals be read?

In general, a confidence interval describes the precision of an estimate under the assumptions of the statistical method. A wider interval indicates less precision than a narrower one. If an interval for a risk difference includes zero, the data are compatible with no difference under that method, as well as with values on either side of zero that remain inside the interval. This does not prove that the groups are the same. Conversely, an interval excluding zero would not, by itself, resolve bias, multiplicity, or clinical importance.

The Phase 2 intervals for serious adverse events and deaths are broad. For serious adverse events, the interval for the 1000mg combination comparison runs from -0.536 to 0.064, and the interval for the LDAC comparison runs from -0.372 to 0.121. For deaths, the corresponding intervals run from -0.308 to 0.275 and from -0.256 to 0.249. These results allow a range of possible differences and do not give a precise ranking of groups. The p-values accompanying these recalculations are unadjusted and should be interpreted in that context.

Why do small groups matter?

General statistical principle: estimates from small groups are often unstable because each participant’s outcome has a comparatively large influence on the observed count. A zero count in a small cohort does not show that the event cannot occur; it means that no qualifying event was recorded in that cohort during the specified period. The registry does not provide a confidence interval for the primary Phase 1 count, so its precision is not quantified in the posted primary result.

General statistical principle: confidence intervals and p-values do not correct for differences between groups, selection processes, missing observations, or changes in outcome ascertainment. Randomization can support causal comparisons when implemented and analyzed appropriately, but the registry record does not report allocation details or a full analysis plan. The open-label design is also relevant because knowledge of assigned treatment can potentially affect reporting or assessment, although the record does not establish that this occurred.

What do the planning illustrations mean?

The posted planning illustrations use observed effects as hypothetical targets and state assumptions of a two-sided significance level of 0.05, equal allocation, and a normal approximation. The rows describe planning for 100%, 75%, or 50% of the observed effect and report participants per arm for 80% or 90% power. These are sample-size planning illustrations, not observed power, not the trial’s original design calculation, and not evidence that the study had adequate power. The registry record does not report that these assumptions were used to plan the actual study.

Planning from an observed effect is especially uncertain when the source groups are small. An observed difference may be larger or smaller than the underlying effect, and an illustration cannot remove that uncertainty. The very large values in some death-outcome planning rows reflect the small observed differences used in those illustrations; they should not be interpreted as required enrollment targets for this trial or as a reconstruction of its protocol.

Why are the primary and secondary outcomes different?

The primary endpoint is a Phase 1 count of dose-limiting toxicities in cycle one. The Phase 2 summaries include any adverse events, serious adverse events, and deaths over a follow-up period extending to a minimum follow-up of up to 2 months. These outcomes differ in definition, clinical seriousness, study phase, and observation window. A comparison of Phase 2 counts cannot replace the primary Phase 1 endpoint, and a zero primary count does not imply that broader adverse events or later deaths did not occur.

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("ULO 600mg + LDAC - Ph1", "ULO 800mg + LDAC - Ph1")
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  ULO 600mg + LDAC - Ph1  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  ULO 800mg + LDAC - Ph1  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 does not report a plan for controlling multiplicity across secondary outcomes or pairwise comparisons. It lists numerous secondary outcomes, including best overall response, adverse events, serious adverse events, deaths, laboratory abnormalities, anti-drug antibodies, and pharmacokinetic concentration. The record also indicates 33 outcome measures and no reported analyses. The listed Phase 2 comparisons have unadjusted p-values, so they should not be interpreted as multiplicity-adjusted evidence.

In general, testing many outcomes or contrasts increases the chance that at least one result appears unusual by chance alone. A prespecified testing hierarchy or adjustment can address some of this issue, but the registry record does not report whether any such approach was used. No conclusion about the trial’s actual analysis procedures should be inferred from the absence of details in the registry.

Missing-data handling is not reported in the registry record. It does not state how participants with incomplete follow-up, unavailable outcome assessments, or withdrawal were handled for each endpoint, nor whether imputation or sensitivity analyses were conducted. The primary endpoint identifies its population as all treated participants, but this does not specify the handling of missing endpoint assessments.

The registry record does not report an intention-to-treat definition, a per-protocol population, or endpoint-specific analysis populations for the Phase 2 comparisons. It also does not provide participant flow by arm or explain how the number evaluated for each outcome was determined. These omissions limit the ability to assess attrition, missingness, and consistency of analysis populations.

These limitations do not mean that missing data or multiplicity necessarily distorted the results. They mean that the registry record does not provide the information needed to evaluate those issues. The available counts and unadjusted comparisons should therefore be interpreted as descriptive and exploratory, particularly for secondary outcomes.

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: febrile neutropenia (66.7%), disseminated intravascular coagulation (33.3%), cardiac failure (33.3%), cataract (33.3%), amylase increased (33.3%).

For Phase 2, serious adverse events were reported in 21 of 26 participants in the ulocuplumab 800mg plus LDAC group, 8 of 14 in the ulocuplumab 1000mg plus LDAC group, and 15 of 22 in the LDAC group. These are participant counts over the registry’s stated period from first dose until a minimum follow-up of up to 2 months. The counts indicate that serious adverse events were recorded across all three groups; they do not identify the cause of every event or establish that treatment assignment caused the event.

The unadjusted recalculated comparisons have wide confidence intervals. The interval for the 1000mg combination comparison includes zero, as does the interval for the LDAC comparison. This means the estimates are imprecise and compatible with a range of possible differences under the calculation method. It does not demonstrate that the groups have identical safety profiles. The registry does not report adjusted sponsor analyses for these comparisons.

Serious adverse events should also be distinguished from the primary dose-limiting toxicity endpoint. The primary outcome required an event to meet the cycle-one, treatment-related definition. Serious adverse events are a separate Phase 2 outcome with a longer specified observation period. The registry’s serious-event counts therefore cannot be used to infer the number of Phase 1 dose-limiting toxicities or to substitute for that endpoint.

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

The primary result means that no dose-limiting toxicities were recorded in either of the two listed Phase 1 cohorts during the first treatment cycle, among the participants counted in those cohorts. It is a limited, time-specific observation from early-phase dose evaluation. It does not establish that ulocuplumab with low dose cytarabine has no dose-limiting toxicity risk, nor does it provide a precise estimate of the risk in a larger population.

It also does not answer whether the combination is effective. Although the registry’s stated purpose includes safety and effectiveness, the primary outcome is a toxicity count, and the posted primary result is not a response or survival estimate. The registry lists best overall response as a secondary outcome in Phase 1, but the record does not provide a result for it. A treatment benefit or lack of benefit cannot be inferred from the primary safety count.

The Phase 2 counts show that adverse events, serious adverse events, and deaths were recorded in each listed group during the stated follow-up. They are descriptive and do not establish comparative safety or effectiveness. The unadjusted comparisons are imprecise, and the registry record does not include sponsor-reported analyses for them. The data also do not establish equivalence between ulocuplumab combination groups and LDAC alone.

The study is recorded as terminated, but the registry record does not report why. That status alone does not explain the termination or indicate how it should affect interpretation of the individual outcomes. Likewise, enrollment and the listed outcome counts do not reveal whether all planned analyses were completed or whether results were selectively reported.

Overall, the result supports only a narrow statement: no participant in either posted Phase 1 dose cohort was counted as having a dose-limiting toxicity during cycle one. Broader conclusions require information and analyses not reported in the registry record, including fuller outcome reporting, analysis methods, missing-data handling, and longer-term follow-up.

14. Why This Trial Matters Statistically

This trial illustrates a central statistical challenge in early-phase studies: a safety event count can be clinically important while remaining imprecise when cohorts are small. Zero observed events is a valid description of the posted Phase 1 results, but it is not the same as precise evidence that the event is absent or exceptionally rare. Interpretation depends on the number observed, the event definition, and the length of follow-up.

It also demonstrates why endpoint definitions matter. The primary outcome is not a count of every toxicity. It applies a treatment-relatedness criterion, a toxicity grading framework, and a cycle-one window. Phase 2 adverse events, serious adverse events, and deaths use different definitions and follow-up. Treating these measures as interchangeable would obscure what each result actually captures.

The registry also highlights the difference between exploratory estimates and reported trial analyses. The Phase 2 risk differences and p-values are unadjusted recalculations from posted counts; the record contains no sponsor-reported analyses for these comparisons. Confidence intervals convey the uncertainty in those estimates, while the lack of reported multiplicity and missing-data procedures limits stronger conclusions.

Finally, planning illustrations based on observed effects are not retrospective proof of power or a record of the original design. They can show how sample-size requirements vary with assumed effect size under stated assumptions, but they cannot compensate for small observed groups or reconstruct a missing protocol rationale. Together, these points make the registry useful for understanding what was recorded while underscoring the boundary between descriptive findings and confirmatory 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.

Several limitations specific to this trial affect interpretation. The primary result comes from small Phase 1 dose cohorts, with 3 participants in each listed group. The absence of dose-limiting toxicities in these cohorts is therefore a limited observation, and the registry does not provide a confidence interval or sponsor-reported inferential analysis for the primary endpoint.

The study combines Phase 1 dose escalation and Phase 2 expansion, but the registry does not describe in detail how randomization operated across the two portions. It identifies the overall design as randomized, open label, and parallel, yet the allocation procedure, ratio, concealment, and any stratification are not reported in the registry record. Open-label assessment may be relevant to reporting or event classification, although the record does not show that it affected the results.

The Phase 2 results are counts over a follow-up period from first dose until a minimum follow-up of up to 2 months. The registry does not provide individual follow-up duration, time-to-event analyses, or detailed participant flow by outcome. Deaths are reported as counts, not as a survival analysis, so timing and censoring cannot be assessed from these summaries.

The registry lists additional outcomes, but does not provide results for all of them in the record. It reports no sponsor analyses for the posted comparisons and does not report a statistical analysis plan, multiplicity handling, missing-data procedures, or endpoint-specific analysis populations beyond the primary all-treated population. The termination status is recorded without an explanation. These gaps prevent assessment of whether the results reflect the full planned analysis and why study conduct ended.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: An Investigational Immuno-therapy Study of Ulocuplumab in Combination With Low Dose Cytarabine in Patients With Newly Diagnosed Acute Myeloid Leukemia — NCT02305563.
• Registry record last updated 2021-09-16; status last verified 2021-08.
• Results first posted 2021-09-16.
• 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 record describes a randomized, open-label, parallel Phase 1/2 study of ulocuplumab with low dose cytarabine in newly diagnosed acute myeloid leukemia. It records enrollment of 70 and a terminated status. Phase 1 included dose-escalation cohorts; Phase 2 included combination groups and an LDAC-only group.

The primary endpoint was the number of treated Phase 1 participants with dose-limiting toxicities during cycle 1, defined as 28 days and assessed using NCI CTCAE v4.03. The posted count was zero in each of the two Phase 1 cohorts, each with 3 participants. Phase 2 results include counts for adverse events, serious adverse events, and deaths over a follow-up period from first dose until a minimum follow-up of up to 2 months.

The registry record does not report sponsor analyses for the comparisons, a statistical analysis plan, missing-data handling, multiplicity procedures, or the reason for termination. The Phase 2 estimates discussed are unadjusted recalculations from posted counts and should be interpreted descriptively.